Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds

ABSTRACT

An aromatic sulfonyl alpha-hydroxy hydroxamic acid compound that, inter alia, inhibits matrix metalloprotease activity is disclosed, as is a treatment process that comprises administering a contemplated aromatic sulfonyl alpha-hydroxy hydroxamic acid compound in an MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

PRIORITY CLAIM TO RELATED PATENT APPLICATIONS

This patent claims priority to International Patent Application No.PCT/US98/042777 (filed on Mar. 4, 1998; and published as InternationalPublication No. WO 98/39326), which in turn, claims priority to U.S.Provisional Patent Application Ser. No. 60/035,182 filed Mar. 4, 1997.

DESCRIPTION

1. Technical Field

This invention is directed to proteinase (protease) inhibitors, and moreparticularly to aromatic sulfonyl alpha-hydroxy hydroxamic acidcompounds that are useful, inter alia, as inhibitors for matrixmetalloproteinases, compositions of those compounds, intermediates forthe syntheses of the compounds, processes for the preparation of thecompounds and processes for treating pathological conditions associatedwith pathological matrix metalloproteinase activity.

2. Background of the Invention

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals make up, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason is involved in a number of disease states.Inhibition of the enzymes responsible for a loss of equilibrium providesa control mechanism for this tissue decomposition and, therefore, atreatment for these diseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes released from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases, or MMPs).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; corneal, epidermal orgastric ulceration; tumor metastasis, invasion or angiogenesis;periodontal disease; proteinuria; multiple sclerosis; Alzheimer'sDisease; coronary thrombosis and bone disease. Defective injury A repairprocesses can also occur. This can produce improper wound healingleading to weak repairs, adhesions and scarring. These latter defectscan lead to disfigurement and/or permanent disabilities as withpost-surgical adhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumornecrosis factor (TNF) and inhibition of the production or action of TNFand related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large number ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

TNF-α convertase is a metalloproteinase involved in the formation ofactive TNF-α. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in WIPO International Publication Nos. WO 94/24140, WO94/02466 and WO 97/20824. There remains a need for effective MMP andTNF-α convertase inhibiting agents. Compounds that inhibit MMPs such ascollagenase, stromelysin and gelatinase have been shown to inhibit therelease of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan etal., Nature 376, 558-561 (1994)).

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin (MMP-3), gelatinase(MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are therelatively most important enzyme or enzymes to inhibit especially whencompared with collagenase I (MMP-1). A drug that does not inhibitcollagenase I can have a superior therapeutic profile. Osteoarthritis,another prevalent disease wherein it is believed that cartilagedegradation in inflamed joints is at least partially caused by MMP-13released from cells such as stimulated chrondrocytes, may be besttreated by administration of drugs one of whose modes of action isinhibition of MMP-13. See, for example, Mitchell et al., J. Clin.Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest.,97:2011-2019 (1996).

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitor of metalloproteinase (TIMP),α₂-macroglobulin and their analogs or derivatives. These are highmolecular weight protein molecules that form inactive complexes withmetalloproteases. A number of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO95/12389,WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMPinhibitors are disclosed in a number of published patent applicationssuch as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 thatdisclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidylback-bones or peptidomimetic back-bones, as does the article by Schwartzet al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. NewDrugs, 15(3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther, 75(1):69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate) indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although marimastat exhibitedsome measure of efficacy via these markers, toxic side effects werenoted. The most common drug-related toxicity of marimastat in thoseclinical trials was musculoskeletal pain and stiffness, often commencingin the small joints in the hands, spreading to the arms and shoulder. Ashort dosing holiday of 1-3 weeks followed by dosage reduction permitstreatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75(1997). It is thought that the lack of specificity of inhibitory effectamong the MMPs may be the cause of that effect.

In view of the importance of hydroxamate MMP inhibitor compounds in thetreatment of several diseases and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be a great benefit if hydroxamates of greater enzyme specificitycould be found. This would be particularly the case if the hydroxamateinhibitors exhibited strong inhibitory activity against one or more ofMMP-2, MMP-9 or MMP-13 that are associated with several pathologicalconditions, while at the same time exhibiting limited inhibition ofMMP-1, an enzyme that is relatively ubiquitous and known to participatein a number of homeostatic processes. The disclosure that followsdescribes one family of hydroxamate MMP inhibitors that exhibit thosedesirable activities.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a family of molecules that interalia inhibit matrix metalloprotease (MMP) activity, and particularlyinhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, whilegenerally exhibiting little activity against MMP-1, as well as a processfor treating a mammal having a condition associated with pathologicalactivity.

Briefly, one embodiment of the present invention is directed to anaromatic sulfonyl alpha-hydroxy hydroxamic acid compound. That compoundcorresponds in structure to Formula I.

wherein

R² is a hydrido, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-₄ hydrocarbyloxymethyl,aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl, (N,N-di-C₁-C₃hydrocarbyl)aminomethyl, (N-morpholino)methyl, (N-pyrrolidino)methyl, or(N-thiomorpholino)methyl group. R² is preferably a hydrido, hydroxy,hydroxymethyl, methoxymethyl or methyl-N-morpholinyl group.

R¹ is a substituent that contains a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length greater than about that of a fullyextended hexyl group and less than about that of a fully extendedeicosyl group. In addition, R¹ defines a three-dimensional volume, whenrotated about an axis drawn through the SO₂-bonded 1-position and the4-position of a 6-membered ring radical or drawn through the SO₂-bonded1-position and the center of 3,4-bond of a 5-membered ring radical,whose widest dimension in a direction transverse to the axis of rotationis about that of one furanyl ring to about that of two phenyl rings.

R¹ preferably contains a single aromatic or heteroaromatic ring that isitself substituted with another substituent, R³. R¹ most preferablycontains a phenyl ring, Ph, that is itself has a substituent, R³, at the4-position. R³ is preferably a phenyl, a phenoxy, a phenylazo, athiophenoxy, an anilino, a benzamido, a nicotinamido, anisonicotinamido, a picolinamido or an ureidophenyl group that can itselfbe substituted at the meta- or para-position or both by a single atom ora substituent containing a longest chain of up to eight atoms, excludinghydrogen.

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anenzyme-inhibiting effective amount to a mammalian host having such acondition. The use of repeated administrations is particularlycontemplated.

Among the several benefits and advantages of the present invention arethe provision of compounds and compositions effective as inhibitors ofmatrix metalloproteinase activity, and the provision of such compoundsand compositions that are effective for the inhibition ofmetalloproteinases implicated in diseases and disorders involvinguncontrolled breakdown of connective tissue.

More particularly, a benefit of this invention is the provision of acompound and composition effective for inhibiting metalloproteinases,particularly MMP-13 and/or MMP-2, associated with pathologicalconditions such as, for example, rheumatoid arthritis, osteoarthritis,septic arthritis; corneal, epidermal or gastric ulceration; tumormetastasis, invasion or angiogenesis; periodontal disease; proteinuria;multiple sclerosis; Alzheimer's Disease; coronary thrombosis and bonedisease.

An advantage of the invention is the provision of a method for preparingsuch compositions. Another benefit is the provision of a method fortreating a pathological condition associated with abnormal matrixmetalloproteinase activity.

Another advantage of the invention is the provision of compounds,compositions and methods effective for treating such pathologicalconditions by selective inhibition of a metalloproteinase such as MMP-13and MMP-2 associated with such conditions with minimal side effectsresulting from inhibition of other proteinases such as MMP-1, whoseactivity is necessary or desirable for normal body function.

Still further benefits and advantages of the invention will be apparentto the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, it has been found that certainaromatic sulfonyl alpha-hydroxy hydroxamic acids (hydroxamates) areeffective for inhibition of matrix metalloproteinases (“MMPs”) believedto be associated with uncontrolled or otherwise pathological breakdownof connective tissue. In particular, it has been found that thesecertain aromatic sulfonyl alpha-hydroxy hydroxamic acids are effectivefor inhibition of collagenase III (MMP-13) and also gelatinase A(MMP-2), which can be particularly destructive to tissue if present orgenerated in abnormal quantities or concentrations, and thus exhibit apathological activity.

Moreover, it has been discovered that many of these aromatic sulfonylalpha-hydroxy hydroxamic acids are selective in the inhibition ofMMP-13, as well as other MMPs associated with diseased conditionswithout excessive inhibition of other collagenases essential to normalbodily function such as tissue turnover and repair. More particularly,it has been found that particularly preferred the aromatic sulfonylalpha-hydroxy hydroxamic acids are particularly active in inhibiting ofMMP-13 and MMP-2, while having a limited or minimal effect on MMP-1.This point is discussed in detail hereinafter and is illustrated in theInhibition Tables hereinafter.

A contemplated compound corresponds to Formula I, below:

wherein

R² is a hydrido, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxymethyl,aminomethyl (NH₂CH₂—), (N—C₁-C₃ hydrocarbyl)aminomethyl, (N,N-di-C₁-C₃hydrocarbyl)aminomethyl [(N—C₁-C₃ hydrocarbyl),(N—C₁-C₃hydrocarbyl)aminomethyl], (N-morpholino)methyl (OC₄H₈NCH₂—),(N-pyrrolidino)methyl (C₄H₈NCH₂—), or (N-thiomorpholino)methyl(SC₄H₈NCH₂—) group. In particularly preferred practice, R² substituentis a methyl, hydroxymethyl, (N-morpholino)methyl or methoxymethyl group.R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length equivalent to a length that is greaterthan about that of a fully extended hexyl group and less than about thatof a fully extended eicosyl group. In addition, R¹ defines athree-dimensional volume, when rotated about an axis drawn through theSO₂-bonded 1-position and the 4-position of a 6-membered ring radical ordrawn through the SO₂-bonded 1-position and the center of 3,4-bond of a5-membered ring radical, whose widest dimension in a directiontransverse to the axis of rotation is about that of one furanyl ring toabout that of two phenyl rings.

As noted above, an R¹ substituent contains a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group. An R¹ substituent also has length,width and substitution requirements that are discussed in detail below.It is noted here, however, that a single-ringed or fused ringcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itselflong enough to fulfill the length requirement. As such, thatcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself besubstituted.

Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl orheteroaryl radicals that can constitute a portion of a R¹ substituentand are themselves substituted as discussed herein include phenyl, 2-,3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl,2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or3-pyrazolidinyl and the like. A phenyl radical is particularly preferredand is used illustratively herein.

When examined along its longest chain of atoms, an R¹ substituent,including its own substituent when present, has a total length that isgreater than that of a fully extended saturated chain of six carbonatoms (a hexyl group); i.e., a length of a heptyl chain or longer, and alength that is less than that of a fully extended saturated chain ofabout 20 carbons (an eicosyl group). Preferably, that length isequivalent to that of a fully extended saturated chain of about 8 toabout 18 carbon atoms, even though many more atoms may be present in theactual ring structures or substituents. This length requirement isdiscussed further below.

Looked at more generally, and aside from specific moieties from which itis constructed, an R¹ substituent (radical, group or moiety) has alength that is equivalent to that of a fully extended heptyl group orgreater. Such an R¹ substituent also has a length that is less than thatof a fully extended eicosyl group. That is to say that a R¹ is asubstituent having a length greater than that of an extended saturatedsix carbon chain and shorter than that of an extended saturated eighteencarbon chain, and more preferably, a length greater than that of anoctyl group and less than that of a palmityl group. The radical chainlengths are measured along the longest linear atom chain in the radical,following the skeletal atoms of a ring where necessary. Each atom in thechain, e.g. carbon, oxygen or nitrogen, is presumed to be carbon forease in calculation.

Such lengths can be readily determined by using published bond angles,bond lengths and atomic radii, as needed, to draw and measure a chain,or by building models using commercially available kits whose bondangles, lengths and atomic radii are in accord with accepted, publishedvalues. Radical (substituent) lengths can also be determined somewhatless exactly by presuming, as is done here, that all atoms have bondlengths of saturated carbon, that unsaturated and aromatic bonds havethe same lengths as saturated bonds and that bond angles for unsaturatedbonds are the same as those for saturated bonds, although theabove-mentioned modes of measurement are preferred. For example, a4-phenyl or 4-pyridyl group has a length of a four carbon chain, as doesa propoxy group, whereas a biphenyl group has a length of about an eightcarbon chain using a contemplated measurement mode.

In addition, an R¹ substituent, when rotated about an axis drawn throughthe SO₂-bonded 1-position and the 4-position of a 6-membered ringradical or the SO₂-bonded 1-position and through the 3,4 bond of a5-membered ring radical defines a three-dimensional volume whose widestdimension has the width of about one furanyl ring to about the width oftwo phenyl rings in a direction transverse to that axis to rotation.

When utilizing this width or volume criterion, a fused ring system suchas a naphthyl or purinyl radical is considered to be a 6- or 5-memberedring that is substituted at appropriate positions numbered from theSO₂-linkage that is deemed to be at the 1-position as discussed before.Thus, a 2-naphthyl substituent or an 8-purinyl substituent is anappropriately sized R¹ radical as to width when examined using the aboverotational width criterion. On the other hand, a l-naphthyl group or a7- or 9-purinyl group is too large upon rotation and is excluded.

As a consequence of these length and width requirements, R¹ substituentssuch as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)phenyl,4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl],4-(phenylazo)phenyl 4-(ureidophenyl)phenyl, 4-(anilino)phenyl,4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl,4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularlypreferred R¹ substituents, with 4-(phenoxy)phenyl and4-(thiophenyl)phenyl being most preferred.

An SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicalis a 5- or 6-membered single-ring that is itself substituted with oneother substituent, R³. The SO₂-linked single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is R³-substituted at its own4-position when a 6-membered ring and at its own 3-position when a5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical to which R³ is bonded is preferably a phenyl group, so that R¹is preferably PhR³ in which R³ is bonded at the 4-position of theSO₂-linked phenyl (Ph) radical, and in which R³ can itself be optionallysubstituted as is discussed hereinafter. Substitution at the 2-positionof a SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical appears to greatly lessen inhibitory potency toward MMP enzymes,and is absent from a contemplated compound.

A contemplated R³ substituent can be a single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl group or another substituent having achain length of 3 to about 14 carbon atoms such as a hydrocarbyl orhydrocarbyloxy group [e.g., C₃-C₁₄ hydrocarbyl or O—C₂-C₁₄ hydrocarbyl],a phenyl group, a phenoxy group [—OC₆H₅], a thiophenoxy group[phenylsulfanyl; —SC₆H₅], an anilino group [—NHC₆H₅], a phenylazo group[—N₂C₆H₅], an ureidophenyl group [aniline carbonylamino;—NHC(O)NH—C₆H₅], a benzamido group [—NHC(O)C₆H₅], a nicotinamido group[3—NHC(O)C₅H₄N], an isonicotinamido group [4—NHC(O)C₅H₄N], or apicolinamido group [2—NHC(O)C₅H₄N]. As noted before in conjunction withthe discussion of R¹, most preferred R³ substituents are phenoxy andthiophenoxy groups that are preferably themselves free of substitution.Additionally contemplated R³ substituent groups include a heterocyclo,heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heteroarylthiogroup.

A contemplated R³ substituent can itself also be substituted with one ormore substituent radicals at the meta- or para-position or both of asix-membered ring with a single atom or a substituent containing alongest chain of up to ten atoms, excluding hydrogen. Exemplarysubstituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro,cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino,arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino,heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl,heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio,heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio,cyclohydrocarbylamino, heteroarylhydrocarbyloxy,heteroarylhydrocarbylthio, heteroarylhydrocarbylamino,arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino,heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy,alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl,hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl,hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio,hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino and N-monosubstituted orN,N-disubstituted aminohydrocarbyl group wherein the substituent(s) onthe nitrogen are selected from the group consisting of hydrocarbyl,aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen andtwo substituents attached thereto form a 5- to 8-membered heterocyclicor heteroaryl ring group.

Thus, initial studies indicate that so long as the length, substitutionand width (volume upon rotation) requirements of an SO₂-linked R¹substituent discussed herein are met, an R¹ substituent can be extremelyvaried.

A particularly preferred R³ substituent of an SO₂-linked Ph group is asingle-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,ureidophenyl, nicotinamido, isonicotinamido, picolinamido, anilino orbenzamido group that is unsubstituted or is itself substituted(optionally substituted) at the para-position when a 6-membered ring orthe 3-position when a 5-membered ring. Here, single atoms such ashalogen moieties or substituents that contain one to a chain of aboutten atoms other than hydrogen such as C₁-C₁₀ hydrocarbyl, C₁-C₉hydrocarbyloxy or carboxyethyl groups can be used.

Exemplary particularly preferred substituted PhR³ (particularlypreferred substituted R¹) substituents include biphenyl,4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-ureidophenyl,4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido.Exemplary particularly preferred R³ groups contain a 6-membered aromaticring and include a phenyl group, a phenoxy group, a thiophenoxy group, aphenylazo group, an ureidophenyl group, an anilino group, a nicotinamidogroup, an isonicotinamido group, a picolinamido group and a benzamidogroup.

More specifically, a particularly preferred sulfonyl butanhydroxamatecompounds has an R³ substituent that is a phenyl group, a phenoxy group,a thiophenoxy group, a phenylazo group, an ureidophenyl group, ananilino group, a nicotinamido group, an isonicotinamido group, apicolinamido group or a benzamido group that is itself optionallysubstituted at its own meta or para-position or both with a moiety thatis selected from the group consisting of a halogen, a C₁-C₉hydrocarbyloxy (—O—C₁-C₉ hydrocarbyl) group, a C₁-C₁₀ hydrocarbyl group,a di-C₁-C₉ hydrocarbylamino [—N(C₁-C₉ hydrocarbyl)(C₁-C₉ hydrocarbyl)]group, a carboxyl C₁-C₈ hydrocarbyl (C₁-C₈ hydrocarbyl-CO₂H) group, aC₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl[C₁-C₄hydrocarbyl-O—(CO)—C₁-C₄ hydrocarbyl] group, a C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl [C₁-C4 hydrocarbyl (CO)—O—C₁-C₄hydrocarbyl] group and a C₁-C₈ hydrocarbyl carboxamido [—NH(CO)—C₁-C₈hydrocarbyl] group, or is substituted at the meta- and para-positions bytwo methyl groups or by a C₁-C₂ alkylenedioxy group such as amethylenedioxy group.

Inasmuch as a contemplated SO₂-linked cyclohydrocarbyl, heterocyclo,aryl or heteroaryl radical is itself preferably substituted with a6-membered aromatic ring, two nomenclature systems are used togetherherein for ease in understanding substituent positions. The first systemuses position numbers for the ring directly bonded to the SO₂-group,whereas the second system uses ortho, meta or para for the position ofone or more substituents of a 6-membered ring bonded to a SO₂-linkedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R³substituent is other than a 6-membered ring, substituent positions arenumbered from the position of linkage to the aromatic or heteroaromaticring. Formal chemical nomenclature is used in naming particularcompounds.

Thus, the 1-position of an above-discussed SO₂-linked cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is the position at which theSO₂-group is bonded to the ring. The 4- and 3-positions of ringsdiscussed here are numbered from the sites of substituent bonding fromthe SO₂-linkage as compared to formalized ring numbering positions usedin heteroaryl nomenclature.

In particularly preferred practice, R¹ contains a phenyl group (Ph)linked at its own 4-position to another substituent, R³, so that R¹ isPhR³, and a contemplated compound has a structure that corresponds toFormula II, below, wherein R² is as before defined and R³ is as definedbelow.

A particularly preferred R³ substituent of an SO₂-linked Ph group is asingle-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,ureidophenyl, nicotinamido, isonicotinamido, picolinamido, anilino orbenzamido group that is unsubstituted or is itself substituted(optionally substituted) at the para-position when a six-membered ringor the 3-position when a five-membered ring. Here, single atoms such ashalogen moieties or substituents that contain one to a chain of aboutten atoms other than hydrogen such as C₁-C₁₀ hydrocarbyl, C₁-C₉hydrocarbyloxy or carboxyethyl groups can be used.

Exemplary particularly preferred substituted R¹ PhR³ substituentsinclude biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl,4-benzamidophenyl, 4-ureidophenyl, 4-anilinophenyl, 4-nicotinamido,4-isonicotinamido, and 4-picolinamido. Exemplary particularly preferredR³ groups contain a six-membered aromatic ring and include a phenylgroup, a phenoxy group, a thiophenoxy group, a phenylazo group, anureidophenyl group, an anilino group, a nicotinamido group, anisonicotinamido group, a picolinamido group and a benzamido group.

In one embodiment of a particularly preferred aromatic sulfonylalpha-hydroxy hydroxamate compound, an R³ substituent is a phenyl,phenoxy, anilino or thiophenoxy group that is itself optionallysubstituted at its own meta or para-position or both with a moiety thatis selected from the group consisting of a halogen, a C₁-C₉hydrocarbyloxy (—O—C₁-C₉ hydrocarbyl) group, a C₁-C₁₀ hydrocarbyl group,a di-C₁-C₉ hydrocarbylamino [—N(C₁-C₉ hydrocarbyl)(C₁-C₉ hydrocarbyl)]group, a carboxyl C₁-C₈ hydrocarbyl (C₁-C₈ hydrocarbyl-CO₂H) group, aC₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl [C₁-C₄hydrocarbyl-O—(CO)—C₁-C₄ hydrocarbyl] group, a C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl [C₁-C₄ hydrocarbyl (CO)—O—C₁-C₄hydrocarbyl] group and a C₁-C₈ hydrocarbyl carboxamido [—NH(CO)—C₁-C₈hydrocarbyl3 group, or is substituted at the meta- and para-positions bytwo methyl groups or by a C₁-C₂ alkylenedioxy group such as amethylenedioxy group. These compounds generally exhibit good activities(IC₅₀ values of about 0.1-60 nM) against MMP-2, MMP-9 and MMP-13, whileexhibiting substantially less activity toward MMP-1 (IC₅₀ values ofabout 1000 to >10,000 nM) An unsubstituted phenoxy or thiophenoxy R³substituent is presently preferred.

In another embodiment of a particularly preferred aromatic sulfonylalpha-hydroxy hydroxamate compound, a R³ substituent is benzamido,nicotinamido, isonicotinamido, picolinamido or ureidophenyl in which thesubstituent ring (benzamido, nicotinamido, isonicotinamido, picolinamidoor ureidophenyl group) is unsubstituted or is itself (optionally)substituted at its own meta- or para-position. A preferred substituentmoiety on the substituent ring is selected from the group consisting ofa halogen, a nitro, a C₁-C₈ hydrocarbyl, C₁-C₇ hydrocarbyloxy, a C₁-C₂alkylenedioxy, an amino, an N—C₂-C₄-hydroxyalkyl-amino [e.g.,—NH(C₄H₈OH)] and an N,N-C₂-C₄-hydroxyalkylamino [e.g.,—N(C₂H₄OH)₂]group. Some of these compounds exhibit more than a100,000-fold difference in in vitro inhibitory activity against MMP-2and MMP-1, and an about 2- to about 100-fold activity enhancementagainst MMP-2 over MMP-13, while still maintaining nanomolar activityagainst MMP-2. These compounds exhibited about a 10- to about 100-foldactivity difference between MMP-2 and MMP-9. Such compounds illustrateone aspect of the activity and selectivity of inhibition of some of thecontemplated compounds.

Inasmuch as a contemplated SO₂-linked aryl or heteroaryl radical isitself preferably substituted with a six-membered aromatic ring, twonomenclature systems are used together herein for ease in understandingsubstituent positions. The first system uses position numbers for thering directly bonded to the SO₂-group, whereas the second system usesortho, meta or para for the position of one or more substituents of asix-membered ring bonded to a SO₂-linked aryl or heteroaryl radical.When a R³ substituent is other than a six-membered ring, substituentpositions are numbered from the position of linkage to the aromatic orheteroaromatic ring. Formal chemical nomenclature is used in namingparticular compounds.

Thus, the 1-position of an above-discussed SO₂-linked aryl or heteroarylradical is the position at which the SO₂-group is bonded to the ring.The 4-and 3-positions of rings discussed here are numbered from thesites of substituent bonding from the SO₂-linkage as compared toformalized ring numbering positions used in heteroaryl nomenclature.

The length, width and the number of aromatic rings present in a R¹substituent bonded to the SO₂ group is believed to play a role in theoverall activity of a contemplated compound against MMP enzymesgenerally. The identity of the R¹ substituent group can also play a rolein the activity of an compound against particular MMP enzymes. Inaddition, substitution at the alpha-position to the hydroxamic acidgroup; i.e., substitution on the carbon atom between the hydroxamic acidgroup and the methylene-SO₂ group, also appears to play a role in thespecificity of a contemplated compound as an inhibitor of specific a MMPenzyme.

For example, the compound of Example 8(N,2-dihydroxy-3-[(4-methoxyphenyl)sulfonyl]propanamide] whoseSO₂-bonded aryl group is a 4-methoxyphenyl substituent having a lengthof about a six carbon chain (a hexyl group) was found to be relativelyinactive as an inhibitor of MMP-1 and only slightly better againstMMP-13. That lack of activity can be compared to the excellent activityexhibited by the compound of Example 9[N,2-dihydroxy-3-1(4-phenoxyphenyl)sulfonyl]-propanamide that issubstituted similarly at the alpha-position, but has a longer R¹ group(an about nine carbon chain). These comparative activities can be seenin Table 51 hereinafter.

The compounds of Examples 14-35 contain PhR3 R¹ groups that include anamido [—C(O)NH—] functionality as part of the R¹ group. Those R¹ groups,depending upon the total length of R¹, appear to somewhat lessen theactivity of the compounds toward MMP-13, while virtually eliminating anyactivity against MMP-1, and thus provide exquisite specificity indistinguishing between those two enzymes. This phenomenon appears tohold whether the R³ group contains an aromatic moiety or an aliphaticmoiety bonded to the amido group and whether the amido group is presentas a —C(O)NH— linkage or part of a ureido [—NHC(O)NH—] linkage. It thusappears as though compounds that contain an amido group-containing R¹substituent are bound minimally, if at all, by MMP-1. These data arealso shown in Table 51 hereinafter.

Those data of Table 51 also show the relative importance of overalllength of the R¹ substituent as well as the relative benefit of thatsubstituent having two aromatic rings. Thus, the compound of Example 24[4-(heptyloxy)-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide],whose R¹ group has a length of about an 18-carbon chain exhibitedpotencies against MMP-13 and MMP-2 that were greater than could bemeasured in the assay, and an activity against MMP-1 that was lower thancould be measured in the assay. Comparison of the data in Table 51 forthe compounds of Examples 16 and 17{N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]benzamideandN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbutanamide}for compounds whose R¹ groups are almost the same length shows thecompound with two aromatic rings to be more active.

It is also preferred that the R¹ substituent contain a thioetherlinkage, as is present in a thiophenoxy R³ group. This preference can beseen by comparison of the activities in Table 51 of similarlysubstituted compounds whose R¹ groups differ in the presence or absenceof a thioether group as in the compounds of Examples 2 and 13 or 9 and12.

A contemplated matrix compound contains an asymmetric carbon atom at thealpha-position so that enantiomeric, d and l or R and S, forms of eachcompound exist. Particularly preferred stereoconfigurations for acontemplated enantiomeric compound are shown below in Formulas III andIV

In the above formulas, the dashed line represents a bond that extendsbeneath the plane of the page, whereas the solid wedge-shaped linerepresents a bond that extends above the plane of the page, as is usualin stereochemical depictions. Where the R² group is methyl, acontemplated compound of Formulas III or IV have the Sstereoconfiguration.

Examination of X-ray crystallographic data of a complex of acontemplated compound bound to MMP-8, an enzyme which is quite similarto MMP-13, indicates that an intramolecular hydrogen bond is formedbetween the alpha-hydroxyl group and a sulfonyl group oxygen of ancompound having the stereoconfiguration shown in Formulas III or IV. Theobservation of this hydrogen bond was unexpected. The conformation ofthe bound inhibitor (Example 1A) appears to allow the intramolecularhydrogen bond for only this stereoisomer. That hydrogen bond cannot formfrom a compound of the opposite configuration while maintaining (a) theorientation of the hydroxamate group toward the metal ion of the enzymeand (b) the position of the R¹ group in the binding pocket of theenzyme. This may account for the better binding of this compound toMMP-13, -2 and -9, compared to a compound of the opposite configuration(compound of Example 1B) (See Table 51 for enzyme data).

Intramolecular hydrogen bonds are well known to those skilled in theart. Although the S stereoisomer of Example 1A is preferred, bothconfigurations permit this favorable intramolecular interaction insolution. The advantages of such intramolecular hydrogen-bonding formedicaments have been reported by several research groups. See, forexample, Smith, et al. J. med. Chem. (1994) 37(2), 215-218 and Leone-Bayet al. J. Med. Chem. (1996) 39(13), 2571-2578.

The data shown in Table 51 illustrate better binding for a compound ofthe above configuration (compound of Example 1A) to MMP-13, -2 and -9than a compound of the opposite configuration (compound of Example 1B).Binding of both compounds to MMP-1 was within about a factor of ten.However, because of the better binding of the compound of Example 1A toMMP-13, the ratio of inhibition of MMP-1 to inhibition of MMP-13 wasabout 2-times greater for the compound of the above stereoconfiguration(Exhibit 1A compound) than for the compound of opposite configuration.The advantages of such intramolecular hydrogen-bonding for medicamentshave been reported by several research groups. See, for example, Smith,et al., J. Med. Chem. (1994) 37(2),215-218 and Leone-Bay et al., J. Med.Chem. (1996) 39(13),2571-2578.

The word “hydrocarbyl” is used herein as a short hand term to includestraight and branched chain aliphatic as well as alicyclic groups orradicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl andalkynyl groups are contemplated, whereas aromatic hydrocarbons such asphenyl and naphthyl groups, which strictly speaking are also hydrocarbylgroups, are referred to herein as aryl groups or radicals, as discussedhereinafter. Where a specific aliphatic hydrocarbyl substituent group isintended, that group is recited; i.e., C₁-C₄ alkyl, methyl or dodecenyl.Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbonatoms, and preferably one to about 10 carbon atoms. A particularlypreferred hydrocarbyl group is an alkyl group.

Usual chemical suffix nomenclature is followed when using the word“hydrocarbyl” except that the usual practice of removing the terminal“yl” and adding an appropriate suffix is not always followed because ofthe possible similarity of a resulting name to one or more substituents.Thus, a hydrocarbyl ether is referred to as a “hydrocarbyloxy” grouprather than a “hydrocarboxy” group as may possibly be more proper whenfollowing the usual rules of chemical nomenclature. On the other hand, ahydrocarbyl group containing a —C(O)O— functionality is referred to as ahydrocarboyl group inasmuch as there is no ambiguity in using thatsuffix. As a skilled worker will understand, a substituent that cannotexist such as a C₁ alkenyl group is not intended to be encompassed bythe word “hydrocarbyl”.

As stated before, a particularly preferred hydrocarbyl group is an alkylgroup. As a consequence, a generalized, but more preferred substituentcan be recited by replacing the descriptor “hydrocarbyl” with “alkyl” inany of the substituent groups enumerated herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyland the like. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples ofalkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

The term “carbonyl”, alone or in combination, means a —C(=O)— groupwherein the remaining two bonds (valences) are independentlysubstituted. The term “thiol” or “sulfhydryl”, alone or in combination,means a —SH group. The term “thio” or “thia”, alone or in combination,means a thiaether group; i.e., an ether group wherein the ether oxygenis replaced by a sulfur atom.

The term “amino”, alone or in combination, means an amine or —NH₂ group,whereas the term mono-substituted amino, alone or in combination, meansa substituted amine —N(H)(substituent) group wherein one hydrogen atomis replaced with a substituent, and disubstituted amine meansa—N(substituent)₂ wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups. Amines, aminogroups and amides are classes that can be designated as primary (I°),secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted ordi-substituted depending on the degree of substitution of the aminonitrogen. Quaternary amine (IV°) means a nitrogen with four substituents(—N⁺(substituent)₄) that is positively charged and accompanied by acounter ion or N-oxide means one substituent is oxygen and the group isrepresented as (—N⁺(substituent)₃—O⁻); i.e., the charges are internallycompensated.

The term “cyano”, alone or in combination, means a —C-triple bond-N(—CN) group. The term “azido”, alone or in combination, means a—N-double bond-N-double bond-N (—N═N═N) group.

The term “hydroxyl”, alone or in combination, means a —OH group. Theterm “nitro”, alone or in combination, means a —NO₂ group.

The term “azo”, alone or in combination, means a —N═N— group wherein thebonds at the terminal positions are independently substituted. The term“hydrazino”, alone or in combination, means a —NH—NH— group wherein theremaining two bonds (valences) are independently substituted. Thehydrogen atoms of the hydrazino group can be replaced, independently,with substituents and the nitrogen atoms can form acid addition salts orbe quaternized.

The term “sulfonyl”, alone or in combination, means a —S(═O)₂— groupwherein the remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a—S(═O)₁— group wherein the remaining two bonds (valences) can beindependently substituted. The term “sulfonylamide”, alone or incombination, means a —S(═O)₂—N═ group wherein the remaining three bonds(valences) are independently substituted. The term “sulfinamido”, aloneor in combination, means a —S(═O)₁N═ group wherein the remaining threebonds (valences) are independently substituted. The term “sulfenamide”,alone or in combination, means a —S—N═ group wherein the remaining threebonds (valences) are independently substituted.

The term “hydrocarbyloxy”, alone or in combination, means an hydrocarbylether radical wherein the term hydrocarbyl is as defined above. Examplesof suitable hydrocarbyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy and the like. The term “cyclohydrocarbyl”, alone or incombination, means a hydrocarbyl radical that contains 3 to about 8carbon fit atoms, preferably from about 3 to about 6 carbon atoms, andis cyclic. Examples of such cyclohydrocarbylhydrocarbyl radicals includecyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl cyclooctynyl and thelike. The term “cyclohydrocarbylhydrocarbyl” means an hydrocarbylradical as defined above which is substituted by a cyclohydrocarbyl asalso defined above.

The term “aryl”, alone or in combination, means a phenyl or naphthylradical that optionally carries one or more substituents selected fromhydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and thelike, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term“arylhydrocarbyl”, alone or in combination, means an hydrocarbyl radicalas defined above in which one hydrogen atom is replaced by an arylradical as defined above, such as benzyl, 2-phenylethyl and the like.The term “arylhydrocarbyloxycarbonyl”, alone or in combination, means aradical of the formula —C(O)—O— arylhydrocarbyl in which the term“arylhydrocarbyl”, has the significance given above. An example of anarylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term“aryloxy” means a radical of the formula aryl-O— in which the term arylhas the significance given above. The term “aromatic ring” incombinations such as substituted-aromatic ring sulfonamide,substituted-aromatic ring sulfinamide or substituted-aromatic ringsulfenamide means aryl or heteroaryl as defined above.

The terms “hydrocarbyloyl” or “hydrocarbylcarbonyl”, alone or incombination, mean an acyl radical derived from an hydrocarbylcarboxylicacid, examples of which include acetyl, propionyl, acryloyl, butyryl,valeryl, 4-methylvaleryl, and the like. The term“cyclohydrocarbylcarbonyl” means an acyl group derived from a monocyclicor bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl,cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionallysubstituted by, for example, a hydrocarbyloylamino group, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms“arylhydrocarbyloyl” or “arylhydrocarbylcarbonyl” mean an acyl radicalderived from an aryl-substituted hydrocarbylcarboxylic acid such asphenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl,4-methoxycinnamoyl and the like.

The terms aroyl or “arylcarbonyl” means an acyl radical derived from anaromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of aheterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group orthe like is a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle that contains one to four hetero atoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and thelike, and/or on a secondary nitrogen atom (i.e., —NH—) by anhydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl orarylhydrocarbyl or on a tertiary nitrogen atom (i.e. ═N—) by oxido andthat is attached via a carbon atom. The tertiary nitrogen atom withthree substituents can also form a N-oxide [═N(O)—] group. Examples ofsuch heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, and the like.

The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or aheteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or thelike is an aromatic monocyclic, bicyclic, or tricyclic heterocycle thatcontains the hetero atoms and is optionally substituted as defined abovewith respect to the definition of heterocyclyl. A “heteroaryl” group isan aromatic heterocyclic ring substituent that can contain one, two,three or four atoms in the ring that are other than carbon. Thoseheteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group cancontain a single five- or 6-membered ring or a fused ring system thatcontains two 6-membered rings or a five- and a 6-membered ring.Exemplary heteroaryl groups include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups;six/5-membered fused ring substituents such as benzothiofuranyl,isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl andanthranilyl groups; and six/6-membered fused rings such as1,2-,1,4-,2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.

The term “cyclohydrocarbylhydrocarbyloxycarbonyl” means an acyl groupderived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of theformula cyclohydrocarbylhydrocarbyl-O—COOH whereincyclohydrocarbylhydrocarbyl has the significance given above. The term“aryloxyhydrocarbyloyl” means an acyl radical of the formulaaryl-O-hydrocarbyloyl wherein aryl and hydrocarbyloyl have thesignificance given above. The term “heterocyclyloxycarbonyl” means anacyl group derived from heterocyclyl-O—COOH wherein heterocyclyl is asdefined above. The term “heterocyclylhydrocarbyloyl” is an acyl radicalderived from a heterocyclyl-substituted hydrocarbylcarboxylic acidwherein heterocyclyl has the significance given above. The term“heterocyclylhydrocarbyloxycarbonyl” means an acyl radical derived froma heterocyclyl-substituted hydrocarbyl-O—COOH wherein heterocyclyl hasthe significance given above. The term “heteroaryloxycarbonyl” means anacyl radical derived from a carboxylic acid represented byheteroaryl-O—COOH wherein heteroaryl has the significance given above.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl,cyclohydrocarbylhydrocarbyl radicals and the like. The term“aminohydrocarbyloyl” means an acyl group derived from anamino-substituted hydrocarbylcarboxylic acid wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsindependently selected from hydrogen, alkyl, aryl, aralkyl,cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine. The term“halohydrocarbyl” means a hydrocarbyl radical having the significance asdefined above wherein one or more hydrogens are replaced with a halogen.Examples of such halohydrocarbyl radicals include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,1,1,1-trifluoroethyl and the like. The term perfluorohydrocarbyl means ahydrocarbyl group wherein each hydrogen has been replaced by a fluorineatom. Examples of such perfluorohydrocarbyl groups, in addition totrifluoromethyl above, are perfluorobutyl, perfluoroisopropyl,perfluorododecyl and perfluorodecyl.

Table 1 through Table 50, below, show several contemplated aromaticsulfonyl alpha-hydroxy hydroxamic acid compounds as structural formulasthat illustrate substituent groups. Each group of compounds isillustrated by a generic formula, followed by a series of preferredmoieties or groups that constitute various substituents that can beattached at the position clearly shown in the generic structure. Thesubstituent symbols, e.g., R¹, are as shown in each Table. One bond(straight line) is shown with those substituents to indicate therespective positions of attachment in the illustrated compound. Thissystem is well known in the chemical communication arts and is widelyused in scientific papers and presentations.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

—H —Ctl₃

TABLE 10

TABLE 11

TABLE 12

TABLE 13

TABLE 14

TABLE 15

TABLE 16

TABLE 17

TABLE 18

TABLE 19

—H —CH₃

TABLE 20

TABLE 21

TABLE 22

TABLE 23

TABLE 24

TABLE 25

TABLE 26

TABLE 27

TABLE 28

TABLE 29

—H —CH₃

TABLE 30

TABLE 31

TABLE 32

TABLE 33

TABLE 34

TABLE 35

TABLE 36

TABLE 37

TABLE 38

TABLE 39

—H —Ctl₃

TABLE 40

TABLE 41

TABLE 42

TABLE 43

TABLE 44

TABLE 45

TABLE 46

TABLE 47

TABLE 48

TABLE 49

—H —CH₃

TABLE 50

Treatment Process

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anMMP enzyme-inhibiting effective amount to a mammalian host having such acondition. The use of administration repeated a plurality of times isparticularly contemplated.

A contemplated compound is used for treating a host mammal such as amouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee orhuman that has a condition associated with pathological matrixmetalloprotease activity.

Also contemplated is the similar use of a contemplated compound in thetreatment of a disease state that can be affected by the activity ofmetalloproteases such as TNF-α convertase. Exemplary of such diseasestates are the acute phase responses of shock and sepsis, coagulationresponses, hemorrhage and cardiovascular effects, fever andinflammation, anorexia and cachexia.

In treating a disease condition associated with pathological matrixmetalloproteinase activity, a contemplated MMP inhibitor compound can beused, where appropriate, in the form of an amine salt derived from aninorganic or organic acid. Exemplary acid salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate.

Also, a basic nitrogen-containing group can be quaternized with suchagents as lower alkyl (C₁-C₆) halides, such as methyl, ethyl, propyl,and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C₈-C₂₀)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromidesand iodides, aralkyl halides like benzyl and phemethyl bromides, andothers to provide enhanced water-solubility. Water or oil-soluble ordispersible products are thereby obtained as desired. The salts areformed by combining the basic compounds with the desired acid.

Other compounds useful in this invention that are acids can also formsalts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Total daily dose administered to a host mammal in single or divideddoses of an MMP enzyme-inhibiting effective amount can be in amounts,for example, of about 0.001 to about 100 mg/kg body weight, preferablyabout 0.001 to about 30 mg/kg body weight daily and more usually about0.01 to about 10 mg. Dosage unit compositions can contain such amountsor submultiples thereof to make up the daily dose. A suitable dose canbe administered, in multiple sub-doses per day. Multiple doses per daycan also increase the total daily dose, should such dosing be desired bythe person prescribing the drug.

The dosage regimen for treating a disease condition with a compoundand/or composition of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

A compound useful in the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.(Easton, Pa.: 1975) and Liberman, H. A. and Lachman, L., eds.,Pharmaceutical Dosage Forms, Marcel Decker (New York, N.Y.: 1980).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, magnesium orcalcium carbonate or bicarbonate. Tablets and pills can additionally beprepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds can be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

Preparation of Useful Compounds

Schemes I-IV and 1-2C hereinbelow illustrate general and specificchemical processes and transformations that can be useful for thepreparation of compounds useful in this invention; i.e., compounds ofFormulas I-IV, with particular emphasis on compounds of Formulas II andIV and similar inhibitors.

A compound of the invention can be produced in accordance with thefollowing synthetic schemes:

Schemes I through IV illustrate general procedures and examples ofchemical transformations useful for the preparation of compounds of thisinvention. Scheme I starts with the conversion of a protected carboxylicacid into a alpha-beta unsaturated protected carboxylic acid wherein R²and R¹ are as defined hereinabove. The preferred reagents arebis-halogenated methanes such as methylene iodide. Bases can be inseveral categories such as are discussed below. Preferred bases arestrong, hindered and/or non-nucleophilic organic bases such metalamides, lithium alkyls or metal hydrides. Preferred solvents are aproticsolvents or dipolar aprotic solvents as discussed below. Most preferredare dipolar aprotic solvents such as DMF.

P represents a carboxylic acid protecting group such as an ester or anacid. P can also represent an —OH group depending upon conditions thatare readily recognized by a person skilled in the art.

The double bond compounds produced by this procedure can be oxidized toepoxides. Oxidation can be direct as with, for example, per-acids orhydrogen peroxide or other similar oxidizing agents such as thosediscussed below. Halohydrin formation with HOCl or halogenation with ahalogen such as chlorine or bromine followed by, for example, basetreatment with a metal hydroxide, can also lead to the desired epoxideby methods well known in the art. In addition, a Darzens type reaction(glycidic acid derivative formation) wherein a alpha-halo carbonylcompound such as a alpha-chloro carboxylic ester is treated with analdehyde or ketone in the presence of base to form the epoxide directly.Preferred bases are non-nucleophilic or moderately nucleophilic basessuch as metal alcoholates, metal amides, magnesium reagents, lithiumreagents or metal hydrides as discussed below.

Scheme I also illustrates opening of an exemplary epoxide intermediateof this invention using a nucleophilic thiol or thiolate reagent.Thiolate nucleophiles can be created by methods well known in the artsuch as treating a thiol with base in situ or by using a preformedthiolate. Use of a pre-formed thiolate can allow maintenance of aprotecting group. These methods are further discussed below as part ofour discussion of the Michael reaction. A preferred base is potassiumhydroxide if hydrolysis of the protecting group is desired or, forexample, a alcoholate such as sodium methoxide if a methyl esterprotecting group is to be maintained in use or an alkyl lithium orlithium amide if maintaining a protecting group is desired.

The product of the nucleophilic ring opening reaction (epoxide ringopening) can be oxidized to the sulfone in one step using twoequivalents of oxidizing agent. The starting material for this reactioncan be a sulfide wherein P is a protecting group such as an ester oramide or a carboxylic acid or where P is OH. Reagents for this processcan include peroxymonosulfate (OXONE®), hydrogen peroxide,meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlacticacid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butylhypochlorite, sodium hypochlorite, hypochlorous acid, sodiummeta-periodate, periodic acid and the like. Protic, non-protic, dipolaraprotic solvents, either pure or mixed, can be chosen, for example,methanol/water.

The oxidation can be carried out at temperature of about −68° to about50° degrees centigrade and normally selected from a range −10° C. toabout 40° C. This oxidation can be carried out in two steps via thesynthesis of sulfoxide which requires the use of only about oneequivalent of one of the above oxidizing agents preferable at about zerodegrees C. The solvents listed above can be used with these selectiveoxidations to a sulfoxide with, for example, methanol or methanol/waterbeing preferred along with a temperature of from about −10° C. to 30° C.It can be desirable in the case of more active oxidizing agents, but notrequired, that the reactions be carried out under an inert gasatmosphere with or without degassed solvents. The sulfoxide is thenoxidized to the sulfone with a second equivalent of oxidizing agent in aseparate step that can be carried out at a stage of the synthesis chosenby a person skilled in the art. Again, at this stage of the synthesis ofthe product compounds, the person skilled in the art can elect to eitherkeep or remove the protecting group by the choice of reagents, solventsand pH conditions. For example, protic solvents or mixed solvents suchas water or water/solvent mixtures under basic conditions can producethe acid directly whereas some peroxy acids in non-protic or dipolaraprotic solvents can oxidize the sulfur without removing the protectinggroup. A preferred oxidizing regent is peroxymonosulfate with thereaction carried out under conditions wherein the preferred protectinggroup, a methyl ester, is hydrolyzed.

Scheme I also illustrates hydroxamate formation to prepare thehydroxamic acid products of this invention. The preferred method in thiscase is direct reaction with hydroxylamine (aq) of an activated esterand diimide coupling. A second preferred method is exchange with, forexample, a methyl ester. This type of reaction is well known in the artespecially the peptide synthesis art and is discussed further below.

Scheme II illustrates the Michael reaction of a thiol such as R¹SH witha protected alpha-beta unsaturated carboxylic acid to form the productsof this invention; i.e., a sulfide amide or ester wherein the amide orester are serving as the carboxylic acid protecting groups. Thisreaction can be base mediated by the use of catalytic amounts of somebases or carried out with an equivalent or more of a base or by theaddition of a preformed thiolate reagent such as a preformed thiol salt.

Non-limiting examples include sodium, potassium, lithium, calcium, ormagnesium salts of thiophenol, substituted thiophenols orheteroarylthiols as defined above. Bases that can be used include, forexample, metal hydroxides such as sodium, potassium, lithium ormagnesium hydroxide, oxides such as those of sodium, potassium, lithium,calcium or magnesium, metal carbonates such as those of sodium,potassium, lithium, calcium or magnesium, metal bicarbonates such assodium bicarbonate or potassium bicarbonate, I°, II° or III° organicamines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines,heterocyclic amines or heteroaryl amines, ammonium hydroxides orquaternary ammonium hydroxides. As non-limiting examples, such aminescan include triethyl amine, trimethyl amine, diisopropyl amine,methyldiisopropyl amine, diazabicyclononane, tribenzyl amine,dimethylbenzyl amine, morpholine, N-methylmorpholine,N,N′-dimethylpiperazine, N-ethylpiperidine,1.1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine and the like. Non-limitingexamples of ammonium hydroxides, usually made from amines and water, caninclude ammonium hydroxide, triethyl ammonium hydroxide, trimethylammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholiniumhydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperaziniumhydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limitingexamples, quaternary ammonium hydroxides can include tetraethyl ammoniumhydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammoniumhydroxide, benzylmethyldiisopropyl ammonium hydroxide,methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammoniumhydroxide, N,N-dimethylmorpholinium hydroxide,N,N,N′,N′,-tetramethylpiperazenium hydroxide, andN-ethyl-N′-hexylpiperidinium hydroxide and the like. Metal hydrides,amide or alcoholates such as calcium hydride, sodium hydride, potassiumhydride, lithium hydride, sodium methoxide, potassium tert-butoxide,calcium ethoxide, magnesium ethoxide, sodium amide, potassiumdiisopropyl amide and the like can also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl, phenyl or butyl lithium, Grignard reagents suchas methylmagnesium bromide or methymagnesium chloride, organocadiumreagents such as dimethylcadium and the like can also serve as bases forcausing salt formation or catalyzing the reaction. Quaternary ammoniumhydroxides or mixed salts are also useful for aiding phase transfercouplings or serving as phase transfer reagents.

The reaction media can consist of a single solvent, mixed solvents ofthe same or different classes or serve as a reagent in a single or mixedsolvent system. The solvents can be protic, non-protic or dipolaraprotic.

Non-limiting examples of protic solvents include water, methanol (MeOH),denatured or pure 95% or absolute ethanol, isopropanol and the like.Typical non-protic solvents include acetone, tetrahydrofurane (THF),dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such asxylene, toluene, or benzene, ethyl acetate, methyl acetate, butylacetate, trichloroethane, methylene chloride, ethylenedichloride (EDC),hexane, heptane, isooctane, cyclohexane and the like. Dipolar aproticsolvents include compounds such as dimethylformamide (DMF),dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea,N-methylpyrrolidone and the like. Non-limiting examples of reagents thatcan be used as solvents or as part of a mixed solvent system includeorganic or inorganic mono- or multi-protic acids or bases such ashydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formicacid, citric acid, succinic acid, triethylamine, morpholine,N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine,potassium hydroxide, sodium hydroxide, alcohols or amines for makingesters or amides or thiols for making the products of this invention andthe like.

Room temperature or less or moderate warming (−10° C. to 60° C.) are thepreferred temperatures of the reaction. If desired, the reactiontemperature can be about −76° C. to the reflux point of the reactionsolvent or solvents.

The beta-SR¹ derivative prepared as discussed above can then be carriedforward as such or oxidized to the corresponding sulfone by methodsdiscussed above. Either of these products can then be reacted undercondensation reaction conditions with an aldehyde or ketone wherein R⁶and R⁷ can be, independently, hydrogen or the groups represented by R²with one less carbon atom; i.e., that carbon atom illustrated in thestructures that is directly attached to the carbon atom alpha to thecarbonyl group. This produces the unsaturated sulfide or sulfonecontaining carboxylic acids or protected carboxylic acids illustrated inScheme II.

The alpha-beta unsaturated sulfide can be oxidized to the sulfonefollowing the condensation as is shown in the scheme. Oxidation ofeither of unsaturated sulfide or sulfone containing carboxylic acids orprotected carboxylic acids to the epoxide containing analogs is alsoillustrated. Oxidation of the sulfide can produce both the epoxide ringand the sulfone in one step.

Hydroxylation of the double bond is also illustrated in Scheme II. Thisprocess is well known in the art and examples reagents for suchconversions include osmium tetroxide, permanganate salts includinghydroxide if desired, iodine with lead acetate, halohydrin formationfollowed by displacement of the halogen with base or its conversion intoan epoxide followed by ring opening with hydroxide or catalytic osmiumtetroxide in the presence of an agent such asN-methyl-morpholine-N-oxide (NMM-N-oxide) for its recycling in situ(re-oxidation) to the tetroxide.

The Schemes illustrate conversion of sulfides or sulfones intohydroxamic acid derivatives wherein P is hydrogen or a protectedintermediate such as an O-arylalkylether, acyl orO-cycloalkoxyalkylether group. In the case of compounds where P═H,treatment with one or more equivalents of hydroxylamine hydrochloride atroom temperature or above in a solvent or solvents such as those listedabove can provide hydroxamic acid compounds of this invention directly.There can be an exchange process also such as that between a methylester and a hydroxylamine that can be further catalyzed by the additionof additional acid. Alternatively, a base such as a salt of an alcoholused as a solvent, for example, sodium methoxide in methanol, can beused to form hydroxylamine in situ which can exchange with an ester oramide.

The exchange can also be carried out with a protected hydroxyl aminesuch as tetrahydropyranylhydroxyamine (THPONH₂), benzylhydroxylamine(BnONH₂), and the like in which case compounds wherein P istetrahydropyranyl (THP) or is benzyl (Bn) are the products. Removal ofthe protecting groups when desired, for example, following furthertransformations in another part of the molecule or following storage, isaccomplished by standard methods well known in the art such as acidhydrolysis of the THP group or reductive removal of the benzyl groupwith hydrogen and a metal catalyst such as palladium, platinum, platinumoxide, palladium on carbon or nickel.

Alternatively, the carboxylic acids of this invention can be convertedinto activated carbonyl compounds using reagents well known in the artincluding the peptide and protein synthesis and amino acid coupling orconjugation art. Examples of such reagents are thionyl chloride, oxalylchloride, phosphorus oxychloride, HOBT, isobutylchloroformate an thelike with or without the use of intermediate condensing agents (carbonylactivating) such as the diimides. These valuable activated carbonylintermediates (acid chlorides, mixed anhydrides and the like) can thenbe transformed into hydroxamic acids or hydroxamic acid derivatives suchas those where P is H, benzyl or THP by condensation with hydroxyl amineor the O-protected hydroxyl amine derivative.

The carboxylic acids of this invention can be prepared and used directlyor, as mentioned above, in a protected form. Protected groups forcarboxylic acids are well known in the art and include such functionalgroups as esters, amides, ortho-esters, and groups generally known asethers such as tetrahydropyranyl ethers or tetrahydropyranyl esters.Alkyl esters such as methyl, ethyl or tert-butyl esters and aralkylesters such as benzyl, benzhydryl and trityl esters are well known inthe art as is their preparation and removal. Amides, either primary,secondary or tertiary, are also well known in the art as are theirpreparation and removal. Many amides and esters are commerciallyavailable. The preferred protecting group is the methyl ester and thepreferred method of conversion of the ester into the acid is via basehydrolysis or the use of a basic reagent or basic conditions in aparticular reaction wherein this conversion is performed in situ in asingle vessel.

Scheme III illustrates another general method of synthesis of thesulfone containing carbonyl compounds of this invention; i.e., use ofthe SN₂ class of reactions. A bimolecular nucleophilic displacement(SN₂) reaction is illustrated where an epoxide ring is opened or anactivated hydroxyl group derivative of a diol is displace or where analcohol is converted into a nucleophilic salt (hydroxyl anion salt) by abase. In the latter example, a preparation of the compounds of thisinvention wherein R² is methoxyalkyl is by conversion of a hydroxylgroup into it alkoxide anion as can be done with base treatment andpreferably using a non-nucleophilic base such as sodium hydride, calciumhydride, potassium hydride or an alkyl lithium or amide reagent. Apreferred base is sodium hydride. A preferred electrophile; i.e.,compound undergoing nucleophilic attack, is an methyl halide or organicsulfonate methyl ester. The most preferred electrophile is methyliodide. The solvents, solvent mixtures or solvent/reagent mixturesdiscussed are satisfactory but non-protic or dipolar aprotic solventssuch as acetone, acetonitrile, DMF and the like are examples of apreferred class. Salts of these amines can be prepared by standardmethods known in the art, e.g., treatment of an amine with HCl to form ahydrochloride salt.

Other SN₂ used in the preparation of compounds of this invention involveconversion of an alcohol of the diols shown in the schemes into aelectrophile such as a halide or a organic sulfonate ester. Examples ofhalides are chlorides, bromides or iodides and their preparation is wellknown in the art. Examples of organic sulfonate esters includetosylates, benzene sulfonates, camphorsulfonates, mesylates andtriflates and their preparation is well known in the art. Preferredhalides are bromides and preferred sulfonates aretrifluoromethanesulfonates (triflates). An example of a method ofpreparing a halide is treatment of a double bone with a hypohalite oropening an epoxide ring with a hydrohalic acid such as HBr, HCl or HI.An example of a method of preparing a sulfonate ester is treatment ofthe alcohol with a base such as a tertiary amine or hindered ornon-nucleophilic base as discussed above to form an alkoxide anionfollowed by the addition of a sulfonic acid anhydride or chloride suchas triflic anhydride or methanesulfonyl chloride. Displacement (SN₂) ofthe halide or sulfonate leaving group with ammonia, an alkyl amine, adi-alkylamine, morpholine, pyrrolidine or thiomorpholine can providecompounds of this invention. Preferred solvents for these reactions arelisted above and include dipolar aprotic solvents such as DMF.

The selection of an atmosphere for the reactions of this Scheme as wellas the other Schemes depends, as usual, a number of variables known tothose skilled in the art. The choices can be an inert atmosphere such asnitrogen, argon, helium and the like or normal or dry air. Preferred isthe use of an inert atmosphere if there is an uncertantity as to therequirements of the process. One of these variables particularlyrequiring the attention of the skilled person is control of oxidation byair or another means of a thiol or the salt of a thiol to itscorresponding disulfide or mixed disulfide. The used of a dampatmosphere while carrying out an organometallic compound requiringsynthesis not desirable for either economic or safety reasons whereasthe use of air is normal for aqueous hydrolysis or exchange reactionswhere oxidation, for example, is not probable.

Protecting groups are used as desired in the preparation of thecompounds of this invention and are discussed above. However, thedecision to use protecting groups or not as well as the selection ofwhich protecting group to use for a particular functional group is basedon a particular objective and is made by a person of ordinary skill inthe art. For example, a factor in the choice of a methyl ester andtert-butyl ester for the protection of a particular carboxylic acidfunction will vary depending upon the preferred method of preparationand the preferred method removal. For example, a methyl ester is knownto be readily hydrolyzed by base or exchanged by an amine or hydroxylamine whereas a tert-butyl ester is relatively resistant to removal bybase or exchange but readily removed by acids. Such protecting groupscan include acyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers,cycloalkyloxy ethers, arylalkyl groups trisubstituted silyl groups andthe like. Examples of such protecting groups include acetyl, THP,Benzyl, Z (benzyloxycarbonyl), tert-butyldimethylsilyl (TBDMS) groupsand the like. Protecting groups are discussed in, for example, Green,T., “protecting Groups in Organic Chemistry”, and other review papersand in other books.

Optically active compound isomers as well as mixed or non-opticallyactive compound isomers are specifically intended to be included in thisdiscussion and as part of this invention. Examples of isomers are RSisomers, enantiomers, diastereomers, racemates, cis isomers, transisomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers andthe like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomersand ortho, meta or para substitution isomers are also included asisomers. Solvates or solvent addition compounds such as hydrates oralcoholates are also specifically included both as chemicals of thisinvention and in, for example, formulations or pharmaceuticalcompositions for delivery.

BEST MODE FOR CARRYING OUT THE INVENTION

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limiting ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 Preparation ofN,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a flask equipped with an overhead stirrer powdered potassiumhydroxide (114.24 g, 2.04 mol) was added to methanol (1 L) over 10minutes. The solution was cooled to zero degrees celsius on an ice bathand methyl 2-methylglycidate (99.2 g, 0.85 mol) in methanol (40 mL) wasadded over 15 minutes. A precipitate formed upon warming to ambienttemperature. After 30 minutes the mixture was cooled to 5° C. and4-(phenoxy)-benzenethiol (151.73 g, 0.75 mol) was added dropwise over 10minutes. The mixture was warmed to ambient temperature. After 24 hoursthe solvent was removed in vacuo. The residue was dissolved into ethylacetate and washed with 3M HCl, and saturated NaCl. Concentration invacuo afforded the sulfide as a solid (256.36 g, quantitative yield).

Part B: A solution of the crude sulfide of Part A (256.3 g, 0.75 moltheoretical) was divided into 3 equal portions. One third (0.25 mol) wasdissolved in THF (1710 mL) and H₂O (190 mL). To this solution was addedOxone® (474 g, 0.77 mol) and the mixture stirred for 1.25 hours. Theexcess Oxone® was removed by filtration and the filtrate wasconcentrated in vacuo. This procedure was repeated 2 times and theproduct was combined and dissolved into ethyl acetate, washed with H₂Oand dried over Na₂SO₄. After concentration in vacuo to 30% volume, thesolution was poured into hexanes. The resulting solid was collected byvacuum filtration. Recrystallization with ethyl acetate/hexanes providedthe sulfone as a white solid (207 g, 83%).

Part C: To a solution of the sulfone of Part B (153.35 g, 455.90 mmol)and N-hydroxybenzotriazole.H₂O (73.86 g, 547.08 mmol) in DMF (1.5 L) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96.14g, 501.49 mmol). After stirring at ambient temperature for 1 hour, thesolution was cooled to 8° C. and NH₂OH_((aq)) (50%, 81 mL, 1.37 mol) wasadded gradually. After 30 minutes at ambient temperature, the DMF wasremoved in vacuo. The residue was dissolved into ethyl acetate andwashed with H₂O and saturated NaCl, and dried over Na₂SO₄.Recrystallization with hot acetone and hexanes provided the titlecompound as a white solid (90 g, 56%). HRMS calculated for C₁₆H₁₇NO₆S:30 352.0855, found 352.0834.

EXAMPLE 1A(S)—N,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide

A solution ofN,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl)propanamide (20 g)in ethanol (1500 mL) was sequentially injected in 12 mL portions onto aProchrom® column (50 mm I.D., 36 mm bed length) packed with Chiralpak®AD. The mobile phase used was 30% isopropyl alcohol/70% heptane.Fractions were collected automatically and pooled. The first elutingpeak was collected and the appropriate fractions were combined toprovide the title compound (8.351 g). HPLC purity: 100%.

EXAMPLE 1B Preparation of(R)—N,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]-propanamide

A solution ofN,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide (20 g)in ethanol (1500 mL) was sequentially injected in 12 mL portions onto aProchrom column (50 mm I.D., 36 mm bed length) packed with Chiralpak AD.The mobile phase used was 30% isopropyl alcohol/70% heptane. Fractionswere collected automatically and pooled. The second eluting peak wascollected and the appropriate fractions were combined to provide thetitle compound (8.176 g). HPLC purity: 92%.

EXAMPLE 2 Preparation ofN,2-dihydroxy-2-(hydroxymethyl)-3-[(4-phenoxyphenyl)-sulfonyl]propanamide

Part A: To a solution of methyl 2-(bromomethyl) acrylate (9.90 g, 55.3mmol) and 4-(phenoxy)-benzenethiol (11.7 g, 57.9 mmol) in acetonitrile(70 mL) was added K₂CO₃ (7.50 g, 54.3 mmol). After stirring at ambienttemperature for 1 hour the solution was concentrated in vacuo to halfvolume and partitioned between ethyl acetate and H₂O. The organic layerwas dried over MgSO₄. Concentration in vacuo provided a yellow liquid. Asolution of the crude liquid in methanol (100 mL) was added to a mixtureof Oxone® (100 g) in methanol (150 mL) and H₂O (25 mL). After 1 hour thesolution was concentrated and partitioned between ethyl acetate and H₂O.The organic layer was washed with H₂O and dried over MgSO₄.Concentration in vacuo provided a thick oil and recrystallization withhot ethyl ether provided the sulfone as a white solid (13.3 g, 73%).

Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in8:1 acetone/water (50 mL) was added osmium tetroxide (2.5% in t-butanol,25 mL, 2.0 mmol) followed by the acrylate of Part A (13.3 g, 40.1 mmol)in 8:1 acetone/water (80 mL). After stirring at ambient temperature for20 hours, Na₂SO₃ (5 g) was added and stirring continued for 1 hour.Concentration in vacuo was followed by partitioning between ethylacetate and H₂O. The organic layer was washed with saturated NaCl.Elution through a silica pad (ethyl acetate) followed by concentrationprovided the diol as a white solid (15 g, quantatitive yield). HRMScalculated for C₁₇H₁₈SO₇S: 367.0852, found 367.0868.

Part C: To a solution of the diol of Part B (2.5 g, 6.8 mmol) in THF (20mL) and methanol (20 mL) was added NH₂OH_((aq)) (50%, 9.0 mL, 138 mmol).After stirring at ambient temperature for 72 hours, additionalNH₂OH_((aq)) (10 mL) was added and stirring continued for 72 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed withsaturated NaCl. The resulting suspension was concentrated in vacuo to aminimal volume and filtration provided the title compound as a whitesolid (1.7 g, 68%). HRMS calculated for C₁₆H₁₇NO₇S: 368.0804, found:368.0759.

EXAMPLE 3 Preparation ofN,α-dihydroxy-α-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-morpholinepropanamide,monohydrochloride

Part A: To a solution of methyl 2-(bromomethyl) acrylate (9.90 g, 55.3mmol) and 4-(phenoxy)-benzenethiol (11.7 g, 57.9 mmol) in acetonitrile(70 mL) was added K₂CO₃ (7.50 g, 54.3 mmol). After stirring at ambienttemperature for 1 hour the solution was concentrated in vacuo to halfvolume and partitioned between ethyl acetate and H₂O. The organic layerwas dried over MgSO₄. Concentration in vacuo provided a yellow liquid. Asolution of the crude liquid in methanol (100 mL) was added to a mixtureof Oxone® (100 g) in methanol (150 mL) and H₂O (25 mL). After 1 hour thesolution was concentrated and partitioned between ethyl acetate and H₂O.The organic layer was washed with 1420 and dried over MgSO₄Concentrationin vacuo provided a thick oil and recrystallization with hot ethyl etherprovided the sulfone as a white solid (13.3 g, 73%).

Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in8:1 acetone/water (5 mL) was added osmium tetroxide (2.5% in t-butanol,25 mL, 2.0 mmol) followed by the sulfone of Part A (13.3 g, 40.1 mmol)in 8:1 acetone/water (80 mL). After stirring at ambient temperature for20 hours, Na₂SO₃ (5 g) was added and stirring continued for 1 hour.After partitioning between ethyl acetate and H₂O, the organic phase wasconcentrated in vacuo. The organic layer was washed with saturated NaCl.Elution through a silica pad (ethyl acetate) followed by concentrationprovided the diol as a white solid (15 g, quantatitive yield).

Part C: To a solution of the diol of Part B (5.48 g, 15.0 mmol) indichloromethane (70 mL), cooled to −78° C., was added pyridine (1.35 mL,16.7 mmol) followed by the slow addition of trifluoromethanesulfonicanhydride (2.71 mL, 16.1 mmol). After stirring for 30 minutes at −78°C., the solution was returned to ambient temperature and stirred for 3hours. The solution was concentrated in vacuo and partitioned betweenethyl acetate and 1M citric acid. The organic layer was washed withsaturated NaCl, dried over MgSO₄, and concentrated in vacuo. The crudematerial was chromatographed on silica gel to obtain a 65:35 mixture ofthe epoxide and triflate, which was carried on to next step withoutadditional purification.

Part D: To a solution of the mixture of epoxide/triflate of Part C (15.0mmol) in methanol (30 mL) cooled to zero degrees C., was addedmorpholine (3.9 mL, 45.0 mmol). The solution was warmed and stirred atambient temperature for 1.5 hours. The solvent was concentrated in vacuoand the residue was dissolved into ethyl acetate and washed with H₂O andsaturated NaCl. Concentration in vacuo provided a yellow, oily foamwhich was dissolved into acetonitrile and concentrated HCl (1 mL) wasadded. Concentration in vacuo followed by trituration with ethyl etherprovided the HCl salt of the morpholine methyl ester compound as a whitesolid (4.2 g, 60%). HPLC purity: >98%.

Part E: To a solution of the methyl ester of Part D (4.1 g, 8.74 mmol)in THF (45 mL) and methanol (45 mL) was added NH₂OH_((aq)) (50%, 5 mL,67.6 mmol) the mixture stirred for 72 hours. The solution wasconcentrated to 25% original volume and partitioned between ethylacetate and H₂O. The organic layer was washed with saturated NaCl, driedover MgSO₄ and concentrated in vacuo. The resulting oil was trituratedwith ethyl acetate/ethyl ether to give a white solid. The HCl salt wasformed by adding HCl (concentrated, 1 mL) to a solution of the free basein acetonitrile (40 mL). Concentration in vacuo followed by triturationwith THF and methanol provided the title compound as a white solid (2.2g, 53%).

EXAMPLE 43-[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]-N,2-dihydroxy-2-(hydroxymethyl)propanamide

Part A: To a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) wasadded K₂CO₃ (33.17 g, 0.24 mol) and the mixture was heated at reflux for8 hours. After concentration of solvent, the residue was dissolved inethyl acetate (400 mL) and washed with H₂O (200 mL), 1N HCl (200 mL) andsaturated NaCl (200 mL) and dried over Na₂SO₄. Recrystallization fromhot ethyl acetate/hexanes provided the acetophenone as a solid (28.5 g,59%). HPLC purity: 99%.

Part B: To a solution of the acetophenone of part A (26.04 g, 108.4mmol) in methanol (590 mL) and H₂O (65 mL) was added Oxone® (133 g,216.7 mmol). The mixture was heated at reflux for 5.5 hours and aftercooling to ambient temperature, the excess Oxone® was removed byfiltration and was washed with methanol. After concentration of solvent,the residue was dissolved in ethyl acetate (400 mL) and washed with H₂O(300 mL) and dried over Na₂SO₄. Purification by chromatography (10%ethyl acetate/hexanes to 20% ethyl acetate/hexanes) provided the phenolas a solid (13.98 g, 60%). HPLC purity: >99%. MS(CI) MH⁺ calculated forC₁₄H₁₄O₂: 215, found 215.

Part C: To a solution of KOH (8 g, 143 mmol) in H₂O (85 mL), cooled tozero degrees C., was added the phenol of Part B (13.7 g, 64.0 mmol)followed by the dropwise addition of dimethylthiocarbamoyl chloride(10.6 g, 85.8 mmol) in THF(75 mL). The solution stirred for 4.5 hours atzero degrees C followed by extraction with toluene (2×125 mL). Theorganic layers were combined and dried over MgSO₄. Purification bychromatography (95:5 hexane/ethyl acetate with 1% triethylamine)provided the thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:>99%.

Part D: The thiocarbamate of Part C (10.9 g, 53.6 mmol) was heated to290° C. for 15 minutes. The compound was cooled to ambient temperatureand dissolved into an 8:1 mixture of ethylene glycol/H₂O. Added to thissolution was added KOH (9.0 g, 161 mmol) and the mixture was stirred for1.5 hours. The mixture was poured over ice (125 g) and concentrated HCl(6 mL) was added. The mixture was extracted with chloroform (1×100 mL)and dichloromethane (2×60 mL) and the combined organic layers were driedover MgSO₄. Purification by chromatography (hexane) provided the 15thiophenol as a colorless liquid (4.0 g, 32%).

Part E: To a solution of the thiophenol of Part D (2.2 g, 9.48 mmol) and2-(bromomethyl)acrylic acid (1.56 g, 9.45 mmol) in acetonitrile (40 mL)was added K₂CO₃ (2.6 g, 18.8 mmol). After stirring for 1 hour, thesolvent was removed in vacuo and the residue was partitioned betweenethyl acetate and 1N HCl. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The crude solid was dissolved in methanol (100mL) and H₂O (8 mL) and Oxone® (16 g, 28.4 mmol) was added. After 90minutes the reaction mixture was filtered to collect excess Oxone® andthe filtrate was concentrated in vacuo. The residue was partitionedbetween ethyl acetate and H₂O and the organic layer was washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided thesulfone as a white solid (2.85 g, 86%).

Part F: To a solution of the sulfone of Part E (2.83 g, 8.1 mmol) and4-methylmorpholine N-oxide (1.9 g, 16.2 mmol) in 8:1 acetone/H₂O (45 mL)was added osmium tetroxide (2.5% in t-butanol, 5 mL, 0.4 mmol) and thesolution stirred for 1.5 hours at ambient temperature. The solvent wasremoved in vacuo and the residue was dissolved in ethyl acetate andacidified with 1N HCl. The aqueous layer was extracted with ethylacetate twice and the combined organic layers were washed with H₂O andsaturated NaCl and dried over MgSO₄. Concentration in vacuo followed bytrituration with ethyl ether provided the diol as an off white solid(2.5 g, 81%).

Part G: To a solution of the diol of Part F (2.4 g, 6.3 mmol) andN-hydroxybenzotriazole.H₂O (1.1 g, 8.2 mmol) in DMF (25 mL) was added1-(3-dimethylamino-propyl)3-ethylcarbodiimide hydrochloride(1.3 g, 6.9mmol). After 1 hour of stirring at ambient temperature, NH2OH_((aq))(50%, 1.25 mL, 21.7 mmol) was added. After 40 minutes the solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. The organic layer was dried over MgSO₄. Triturationwith a combination of ethyl ether, isopropanol, methanol and THFprovided the title compound as a white solid (750 mg, 30%). HRMScalculated for C₁₈H₂₁NO₇S: 396.1117, found 396.1125.

EXAMPLE 53-[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]-N,2-dihydroxy-2-methylpropanamide

Part A: To a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) wasadded K₂CO₃ (33.17 g, 0.24 mol) and the mixture was heated at reflux for8 hours. After concentration of solvent the residue was dissolved inethyl acetate (400 mL) and H₂O (200 mL), washed with 1N HCl (200 mL) andsaturated NaCl (200 mL) and dried over Na₂SO₄. Recrystallization fromhot ethyl acetate/hexanes provided the acetophenone as a solid (28.5 g,59%). HPLC purity: 99%.

Part B: To a solution of the acetophenone of part A (26.04 g, 108.4mmol) in methanol (590 mL) and H₂O (65 mL) was added Oxone® (133 g,216.7 mmol). The mixture was heated at reflux for 5.5 hours and aftercooling to ambient temperature, the excess Oxone® was removed byfiltration and was washed with methanol. After concentration of themethanol the residue was dissolved in ethyl acetate (400 mL) and washedwith H₂O (300 mL) and dried over Na₂SO₄. Purification by chromatography(10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) provided thephenol as a solid (13.98 g, 60%). HPLC purity: >99%. MS(CI) MH⁺calculated for C₁₄H₁₄O₂: 215, found: 215.

Part C: To a solution of KOH (8 g, 143 mmol) in H₂O (85 mL), cooled tozero degrees C., was added the phenol of Part B (13.7 g, 64.0 mmol)followed by the dropwise addition of dimethylthiocarbamoyl chloride(10.6 g, 85.8 mmol) in THF (75 mL). The solution stirred for 4.5 hoursat zero degrees C. followed by extraction with toluene (2×125 mL). Theorganic layers were combined and dried over MgSO₄. Purification bychromatography (95:5 hexane/ethyl acetate with 1% triethylamine)provided the thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:>99%.

Part D: The thiocarbamate of Part C (10.9 g, 53.6 mmol) was heated to290° C. for 15 minutes. The compound was cooled to ambient temperatureand dissolved into an 8:1 mixture of ethylene glycol/H₂O. Added to thissolution was KOH (9.0 g, 161 mmol) and 15 the mixture stirred for 1.5hours. The mixture was poured over ice (125 g) and concentrated HCl (6mL) was added. The mixture was extracted with chloroform (1×100 mL) anddichloromethane (2×60 mL) and the combined organic layers were driedover MgSO₄. Purification by chromatography (hexane) provided the thiolas a colorless liquid (4.0 g, 32%).

Part E: To a solution of KOH (1.14 g, 20.4 mmol) in methanol (10 mL)cooled to zero degrees C. was added methyl 2-methylglycidate (0.9 mL,8.5 mmol). The solution was warmed and stirred for 30 minutes at ambienttemperature. The solution was again cooled to zero degrees C. and addedto it was the thiol of Part D (1.78 g, 7.73 mmol). The solution stirredfor 24 hours at ambient temperature. After concentration to removesolvent, the residue was dissolved into ethyl acetate and acidified with1N HCl. The organic layer was washed with saturated NaCl and dried overNa₂SO₄. Concentration in vacuo provided the sulfide as a solid (3.2 g,quantitative yield). HPLC purity: 99%.

Part F: To a solution of the sulfide of Part E (2.6 g, 7.8 mmol) in THF(59 mL) and H₂O (6 mL) was added Oxone® (14.4 g, 23.5 mmol) and themixture stirred for 1 hour. The excess Oxone® was collected byfiltration and washed with THF. The filtrate was concentrated and theresidue was dissolved in ethyl acetate, washed with H₂O and dried overNa₂SO₄. Concentration in vacuo provided the sulfone as a solid (2.83 g,quantitative yield). HPLC purity: 99%. MS(CI) MH⁺ calculated forC₁₈H₂₀O₆S: 365, found 365.

Part G: To a solution of the acid of Part F (2.74 9, 7.52 mmol) andN-hydroxybenzotriazole.H₂O (1.22 g, 9.02 mmol) in DMF (25 mL) was added1-(3-dimethylamino-propyl)3-ethylcarbodiimide hydrochloride (1.59 g,8.27 mmol). After stirring at ambient temperature for 1 hour, NH₂OH(,q)(50%, 1.3 mL, 22.56 mmol) was added. After 15 minutes the solvent wasremoved in vacuo and the residue was dissolved in ethyl acetate, washedwith H₂O and saturated NaCl, and dried over Na₂SO₄. Recrystallizationwith hot acetone/hexane provided the title compound as a white powder(1.35 g, 47%). HPLC purity: 99%. MS(CI) MH⁺ calculated for C₁₈H₂₁NO₆S:380, found 380.

EXAMPLE 6N,2-dihydroxy-2-(methoxymethyl)-3-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a solution of methyl 2-(bromomethyl) acrylate (9.90 g, 55.3mmol) and 4-5 (phenoxy)benzenethiol (11.7 g, 57.9 mmol) in acetonitrile(70 mL) was added K₂CO₃ (7.50 g, 54.3 mmol). After stirring at ambienttemperature for 1 hour the solution was concentrated in vacuo to halfvolume and partitioned between ethyl acetate and H₂O. The organic layerwas dried over MgSO₄. Concentration in vacuo provided a yellow liquid. Asolution of the crude liquid in methanol (100 mL) was added to Oxone®(100 g) in a mixture of methanol (150 mL) and H₂O (25 mL). After 1 hour,the solution was concentrated and partitioned between ethyl acetate andH₂O. The organic layer was washed with H₂O and dried over MgSO₄.Concentration in vacuo provided a thick oil, and recrystallization withhot ethyl ether provided the sulfone as a white solid (13.3 g, 73%).

Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in8:1 acetone/water (50 mL) was added osmium tetroxide (2.51 in t-butanol,25 mL, 2.0 mmol) followed by the acrylate of Part A (13.3 g, 40.1 mmol)in 8:1 acetone/water (80 mL). After stirring at ambient temperature for20 hours, Na₂SO₃ (5 g) was added and stirring continued for 1 hour.Concentration in vacuo was followed by partitioning between ethylacetate and H₂O. The organic layer was washed with saturated NaCl.Elution through a silica pad (ethyl acetate) followed by concentrationprovided the diol as a white solid (15 g, quantatitive yield).

S Part C: To a solution of the methyl ester of Part B (535 mg, 1.46mmol) in DMF (20 mL), cooled to zero degrees C., was added NaH (66 mg,4.7 mmol). After stirring for 5 minutes, iodomethane (505 mg, 8.14 mmol)was added. After stirring for 70 minutes, the solution was purified viaflash chromatography (50/50 ethyl acetate/hexanes to 100 ethyl acetate)providing the methyl ether as a foam (262 mg, 47%).

Part D: To a solution of the methyl ester of Part C (260 mg, 0.68 mmol)in THF (1.5 mL) and methanol (1.5 mL) was added NH₂₀H(aq) (50%, 1 mL,13.6 mmol) and the solution stirred for 20 hours at ambient temperature.An additional 1.5 mL of NH₂OH_((aq)) were added and the solution stirredfor 96 hours. The solution was partitioned between ethyl acetate andH₂O, the organic was dried over MgSO₄ and concentrated in vacuo to givethe title compound as a foam (20 mg, 8%).

EXAMPLE 7α-[[[4-(3,4-dimethylphenoxy)-phenyl]sulfonyl]methyl]-N-2-dihydroxy-4-morpholineproanamide

Part A: To a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) wasadded K₂CO₃ (33.17 g, 0.24 mol) and the mixture heated at reflux for 8hours. After concentration of solvent the residue was dissolved in ethylacetate (400 mL) and H₂O (200 mL), washed with IN HCl (200 mL) andsaturated NaCl (200 mL) and dried over Na₂SO₄. Recrystallization fromhot ethyl acetate/hexanes provided the acetophenone as a solid (28.5 g,59t). HPLC purity: 99%.

Part B: To a solution of the acetophenone of part A (26.04 g, 108.4mmol) in methanol (590 mL) and H₂O (65 mL) was added Oxone® (133 g,216.7 mmol). The mixture was heated at reflux for 5.5 hours and aftercooling to ambient temperature, the excess Oxone® was removed byfiltration and was washed with methanol. After concentration of solvent,the residue was dissolved in ethyl acetate (400 mL) and washed with H₂O(300 EL) and dried over Na₂SO₄. Purification by chromatography (10%ethyl acetate/hexanes to 20% ethyl acetate/hexanes) provided the phenolas a solid (13.98 g, 60%). HPLC purity: >99%. MS(CI) MH⁺ calculated forC₁₄H₁₄O₂: 215, found: 215.

Part C: To a solution of KOH (8 g, 143 mmol) in H₂O (85 mL), cooled tozero degrees C., was added the phenol of Part B (13.7 g, 64.0 mmol)followed by the dropwise addition of dimethylthiocarbamoyl chloride(10.6 g, 85.8 mmol) in THF(75 ml). The solution was stirred for 4.5hours at zero degrees C. followed by extraction with toluene (2×125 mL).The organic layers were combined and dried over MgSO₄. Purification bychromatography (95:5 hexane/ethyl acetate with 1% triethylamine)provided the thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:>99%.

Part D: The thiocarbamate of Part C (10.9 g, 53.6 mmol) was heated to290° C. for 15 minutes. The compound was cooled to ambient temperatureand dissolved into an 8:1 mixture of ethylene glycol/H₂O. Added to thissolution was KOH (9.0 g, 161 mmol) and the mixture was stirred for 1.5hours. The mixture was poured over ice (125 g) and concentrated HCl (6mL) was added. The mixture was extracted with chloroform (1×100 mL) anddichloromethane (2×60 mL) and the combined organic layers were driedover MgSO₄. Purification by chromatography (hexane) provided thethiophenol as a colorless liquid (4.0 g, 32%).

Part E: To a solution of the thiophenol of Part D (2.2 g, 9.48 mmol) and2-(bromomethyl)acrylic acid (1.56 g, 9.45 mmol) in acetonitrile (40 mL)was added K₂CO₃ (2.6 g, 18.8 mmol). After stirring for 1 hour, thesolvent was removed in vacuo and the residue was partitioned betweenethyl acetate and 1N HCl. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The crude solid was dissolved in methanol (100mL) and H₂O (8 mL) and Oxone® (16 g, 28.4 mmol) was added. After 90minutes, the reaction mixture was filtered to collect excess Oxone® andthe filtrate was concentrated in vacuo. The residue was partitionedbetween ethyl acetate and H₂O, the organic layer was washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided thesulfone as a white solid (2.85 g, 92%).

Part F: To a solution of the sulfone of Part E (45.0 g, 129.9 mmol) inmethanol (600 mL) was added thionyl chloride (19 mL, 259.8 mmol)dropwise. The solution was heated at reflux for 3 hours. The solutionwas concentrated in vacuo and the residue was partitioned between ethylacetate and saturated NaHCO₃. The aqueous solution was extracted oncewith ethyl acetate and the organic layers were combined and washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided themethyl ester as a tan oil (45.8 g, 98%). Compound carried on to nextstep without additional purification. HPLC purity: 92%.

Part G: To a solution of 4-methylmorpholine N-oxide (29.3 g, 249.71mmol) in 8:1 acetone/H₂O (100 mL) was added osmium tetroxide (2.5% int-butanol, 15.65 mL, 1.25 mmol) followed by the dropwise addition of themethyl ester of Part F (45.0 g, 125 mmol) in 8:1 acetone/H₂O. Thesolution stirred for 1 hour at ambient temperature. To the mixture isadded Na₂CO₃ (16 g) and stirring continued for 30 minutes. The solutionwas concentrated in vacuo and the residue was partitioned between ethylacetate/H₂O. The aqueous layer was extracted once with ethyl acetate andthe organic layers were combined, washed with brine, and dried overMgSO₄. Purification by chromatography (ethyl acetate/hexane) providedthe diol as a white solid (41.6 g, 85%).

Part H: To a solution of the diol of Part G (3.0 g, 7.61 mmol) indichloromethane (38 mL) cooled to −71° C. was added pyridine (0.69 mL,8.52 mmol) followed by the slow addition of triflic anhydride (1.4 mL,7.99 mmol). The solution stirred at −71° C. for 25 minutes. Additionalpyridine (69 mL, 8.52 mmol) and trifluoromethanesulfonic anhydride (1.4mL, 7.99 mmol) were added and the solution stirred for 1 hour. Thesolution was partitioned between ethyl acetate and citric acid (5%). Theorganic layer was washed with saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the triflate as an oil (4.27 g,quantitative yield).

Part I: To a solution of the triflate of Part H (4.27 g, 8.11 mmol) inTHF (15 mL), cooled to zero degrees C., was added morpholine (2.1 mL,24.33 mmol). The solution stirred at ambient temperature for 1.5 hours.The solvent was removed in vacuo and the residue was dissolved intoethyl acetate and washed with saturated NaHCO₃, saturated NaCl and driedover Na₂SO₄. After concentration, the residue was dissolved inacetonitrile and acidified with concentrated HCl. Trituration with ethylether provided the ethyl morpholine compound as a white solid (2.95 g,73%).

Part J: To a solution of the ethyl morpholine of Part I (2.95 g, 5.89mmol) in 1:1 THF/methanol (14 mL) was added NH₂₀H_((aq)) (50%, 7 mL, 118mmol). After stirring at ambient temperature for 20 hours additionalNH₂OH_((aq)) (7 mL) was added and the solution stirred for an additional24 hours. After concentration in vacuo the residue was dissolved intoethyl acetate and washed with saturated NaHCO₃, H₂O, and saturated NaCland dried over Na₂SO₄. The solution was acidified with concentrated HCland trituation with ethyl ether provided a crude solid.Recrystallization with hot THF and ethyl ether providedα-[[[4-(3,4-dimethylphenoxy)-phenyl]sulfonyl]methyl]-N-2-dihydroxy-4-morpholine-propanamideas a white solid (1.5 g, 51%). HPLC purity: 98%. MS (CI) MH⁺ calculatedfor C₂₂H₂₈N₂O₇.HCl: 465, found: 465.

EXAMPLE 8 N,2-dihydroxy-3-[(4-methoxyphenyl)sulfonyl[propanamide

Part A: To a solution of β-chlorolactic acid (2.0 g, 16.1 mmol) in DMF(45 mL) was added 4-methoxy-benzenethiol (2.0 mL, 16.1 mmol) and K₂CO₃(4.4 g, 31.8 mmol) and the solution was stirred for 1 hour at ambienttemperature. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and 1N HCl. The organic layer wasdried over MgSO₄ and concentrated in vacuo. To a solution of the crudesulfide in methanol (100 mL) and H₂O (5 mL) was added Oxone® (30 g, 48.3mmol) and the mixture was stirred for 18 hours at ambient temperature.The mixture was filtered and the filtrate was acidified to pH=7 withaqueous K₂CO₃. The solution was partitioned between ethyl acetate andH₂O and the organic layer was washed with saturated NaCl, dried overMgSO₄ and concentrated in vacuo. Chromatography (ethyl acetate/hexane)provided the sulfone methyl ester as a clear, colorless oil (2.3 g,52%).

Part B: To a solution of the sulfone of part A (2.3 g, 8.4 mmol) inmethanol (25 mL) and THF (25 mL) was added 50% aqueous hydroxylamine(5.7 mL, 84 mmol) and the solution was stirred for 1 hour. The solutionwas diluted with ethyl acetate and concentration in vacuo providedN,2-dihydroxy-3-[(4-methoxyphenyl)sulfonyl]propanamide as a white powder(1.75 g, 76%). HPLC purity: >99%. HRMS calculated for C₁₀H₁₃NO₆S:276.0542, found. 276.0546.

EXAMPLE 9 N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF(85 mL) was added 4-fluorothiophenol (10.3 g, 80.3 mmol) and K₂CO₃ (22g, 16 mmol) and the solution was stirred for 1 hour at ambienttemperature. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and 1N HCl. The sulfide-containingorganic layer was dried over MgSO₄ and concentrated in vacuo. To asolution of the crude sulfide in methanol (250 mL) and H₂O (100 mL) wasadded Oxone® (149 g, 240 mmol) and the mixture was stirred for 6 hoursat ambient temperature. The mixture was filtered, the filtrate wasconcentrated and trituration with ethyl ether provided the sulfone as awhite solid (19 g, 91%).

Part B: To a solution of the sulfone of part A (1.0 g, 4.3 mmol) in DMF(45 mL) was added phenol (633 mg, 6.45 mmol) and K₂CO₃ (1.8 g 12.9 mmol)and the solution was heated at 60° C. for 18 hours. The solution wasconcentrated in vacuo and the residue was dissolved into methanol andHCl gas was bubbled into the solution to form the methyl ester.Concentration in vacuo provided the methyl ester as a white solid (630mg, 43

Part C: To a solution of the methyl ester of part B (630 mg, 1.9 mmol)in methanol (4 mL) and THF (4 mL) was added 50% aqueous hydroxylamine(1.4 mL, 19 mmol) and the solution stirred for 18 hours. The solutionwas concentrated in vacuo and the residue was partitioned between ethylacetate and aqueous KHSO₄. The organic layer was washed with saturatedNaCl and dried over MgSO₄. Chromatography (ethyl acetate/methanol)provided N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide as whitesolid (250 mg, 40%) HPLC purity: >97%. HRMS calculated for C₁₅H₁₅NO₆S:338.0698, found: 338.0678.

EXAMPLE 10 (R)—N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a solution of D-serine (25.0 g, 237.9 mmol) in 6N HCl (300mL) cooled to zero degrees C. was added sodium nitrite (19.0 g, 275mmol) and the solution was stirred for 3.5 hours. The solution wasextracted with ethyl ether and the combined chloro compound-containingorganic layers were dried over Na₂SO₄. Concentration in vacuo providedthe chloro compound as a yellow oil (15.2 g, 51%).

Part B: To a solution of the chloro compound of part A (15.2 g, 122.1mmol) in ethanol (75 mL) cooled to zero degrees C. was added crushed KOH(13.7 g, 244.13 mmol). The solution stirred for 18 hours at ambienttemperature. The reaction was filtered and the filtrate was concentratedin vacuo to provide the epoxide as a light yellow solid (11.9 g, 77 p).

Part C: To a solution of 4-(phenoxy)benzenethiol (4.0 g, 19.8 mmol) inmethanol (35 mL) cooled to zero degrees C. was added the epoxide of partB (2.5 g, 19.8 mmol) followed by sodium methoxide (preformed with 500 mgsodium in 50 mL methanol). The solution was heated at 40° C. for 24hours. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and 1N HCl. The organic layer waswashed with saturated NaCl and dried over MgSO₄. Concentration in vacuoprovided the crude sulfide as a tan solid (5.7 g).

Part D: To a solution of the sulfide of part C (5.7 g, 19.7 mmol) inmethanol (100 mL) was added thionyl chloride (2.9 mL, 39.3 mmol) and thesolution was heated at reflux for 1 hour. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate andsaturated NaHCO₃. The aqueous layer was extracted with ethyl acetate andthe combined organic layers were washed with saturated NaCl and driedover MgSO₄. Chromatography (ethyl acetate/hexane) provided the methylester as a colorless oil (3.8 g,

Part E: To a solution of the sulfide of part D (3.76 g, 12.3 mmol) inmethanol (90 mL) and H₂O (10 mL) was added Oxone® (26.6 g, 43.2 mmol)and the solution was stirred for 16 hours at ambient temperature. Themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was partitioned between ethyl acetate and H₂O. The aqueous layerwas extracted with ethyl acetate and the combined organic layers werewashed with saturated NaCl and dried over MgSO₄. Concentration in vacuoprovided the sulfone as a white solid (3.9 g, 93%).

Part F: To a solution of the sulfone of part E (3.9 g, 11.6 mmol) inmethanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14mL). The solution was stirred for 16 hours at ambient temperature. Thesolution was concentrated in vacuo and recrystallization (acetone/H₂O)provided (R)—N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide as awhite solid (2.6 g, 67%). HPLC purity: 99%. HRMS calculated forC₁₅H₁₅NO₆S: 338.0698, found: 338.0673.

EXAMPLE 11 (S)—N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide

Part A: To a solution of L-serine (25.0 g, 237.9 mmol) in 6N HCl (300mL) cooled to zero degrees C. was added sodium nitrite (19.0 g, 275mmol) and the solution was stirred for 3.5 hours. The solution wasextracted with ethyl ether and the combined organic layers were driedover Na₂SO₄. Concentration in vacuo provided the chloro compound as ayellow oil (19.7 g, 67%).

Part B: To a solution of the chloro compound of part A (19.7 g, 160.6mmol) in ethanol (50 mL) cooled to zero degrees C. was added crushed KOH(14 g, 249.5 mmol). The solution stirred for 18 hours at ambienttemperature. The reaction was filtered and the filtrate was concentratedin vacuo followed by trituration with ethyl ether provided the epoxideas a light yellow solid (14.1 g, 70%).

Part C: To a solution of 4-(phenoxy)benzenethiol (4.0 g, 19.8 mmol) inmethanol (35 mL) cooled to 0° C. was added the epoxide of part B (3.1 g,24.7 mmol) followed by sodium methoxide (preformed with 600 mg sodium in50 mL methanol). The solution was heated at 40° C. for 24 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and 1N HCl. The organic layer was washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided thecrude sulfide as a tan solid (7.3 g, 86%).

Part D: To a solution of the sulfide of part C (5.7 g, 19.7 mmol) inmethanol (100 mL) was added thionyl chloride (2.9 mL, 39.3 mmol) and thesolution was heated at reflux for 1 hour. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate andsaturated NaHCO₃. The aqueous layer was extracted with ethyl acetate andthe combined organic layers were washed with saturated NaCl and driedover MgSO₄. Chromatography (ethyl acetate/hexane) provided the methylester as a colorless oil (4.1 g, 84%).

Part E: To a solution of the methyl ester of part D (4.1 g, 13.5 mmol)in methanol (100 mL) and H₂O (20 mL) was added Oxone® (29.0 g, 47.2mmol) and the solution was stirred for 72 hours at ambient temperature.The mixture was filtered and the filtrate was concentrated in vacuo. Theresidue was partitioned between ethyl acetate and H₂O. The aqueous layerwas extracted with ethyl acetate and the combined organic layers werewashed with saturated NaCl and dried over MgSO₄. Concentration in vacuoprovided the sulfone as a white solid (4.4 g, 98%).

Part F: To a solution of the sulfone of part E (3.9 g, 11.6 mmol) inmethanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14mL). The solution was stirred for 18 hours at ambient temperature. Thesolution was concentrated in vacuo and recrystallization (acetone/H₂O)provided (S)—N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide as awhite solid (3.0 g, 77%). HPLC purity: 97.6%. HRMS calculated forC₁₅H₁₅NO₆S: 338.0698, found: 338.0748.

EXAMPLE 12 N,2-dihydroxy-3-[[4-(phenylthio)phenyl]sulfonyl]propanamide

Part A: To a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF(85 mL) was added 4-fluorothiophenol (10.3 9, 80.3 mmol) and K₂CO₃ (22g, 16 mmol) and the solution was stirred for 1 hour at ambienttemperature. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and1N HCl. The organic layer was driedover MgSO₄ and concentrated in vacuo. To a solution of the crude sulfidein methanol (250 mL) and H₂O (100 mL) was added Oxone® (149 g, 240 mmol)and the mixture was stirred for 6 hours at ambient temperature. Themixture was filtered, the filtrate was concentrated and trituration withethyl ether provided the sulfone as a white solid (19 g, 91%).

Part B: To a solution of the sulfone of part A (7.4 g, 34.3 mmol) in DMF(70 mL) was added thiophenol (6.6 mL, 68.6 mmol) and K₂CO₃ (11.8 g, 85.5mmol) and the solution was heated at 600 C for 18 hours. The reactionwas concentrated and the residue was partitioned between ethyl acetateand1N HCl. The organic layer was dried over MgSO₄ and concentrated invacuo. The crude acid was dissolved into methanol (250 mL) and wastreated with thionyl chloride (3.0 mL, 41.2 mmol). The solution wasstirred for 72 hours at ambient temperature. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. The organic layer was washed with saturated NaCl anddried over MgSO₄. Concentration in vacuo followed by trituration withethyl provided the sulfone methyl ester as a white solid (5.9 g, 49%).

Part C: To a solution of the sulfone methyl ester of part B (2.1 g, 6.0mmol) in methanol (20 mL) and THF (20 mL) was added 50t aqueoushydroxylamine (3.5 mL, 60 mmol) and the solution stirred for 18 hours atambient temperature. Filtration of the resulting precipitate providedN,2-dihydroxy-3-[[4-(phenylthio)phenyl]-sulfonyl]propanamide as a whitesolid (1.4 g, 66%). HPLC purity: >98%. HRMS calculated for C₁₅H₁₅NO₅S₂:354.0470, found: 354.0465.

EXAMPLE 13N,2-dihydroxy-2-hydroxymethyl)-3-[[4-(phenylthio)phenyl]sulfonyl]propanamide

Part A: To a solution of 2-(bromomethyl)-acrylic acid (12.9 g, 78.0mmol) and 4-fluorothiophenol (10.0 g, 78.0 mmol) in acetonitrile (400mL) was added K₂CO₃ (21.6 g, 156 mmol). The solution was stirred for 1hour at ambient temperature and then concentrated in vacuo. The residuewas partitioned between ethyl acetate and 1N HCl. The organic layer waswashed with saturated NaCl and dried over MgSO₄. Concentration in vacuoprovided the sulfide as a yellow solid (16.2 g, 98%).

Part B: To a solution of the sulfide of part A (16.2 g, 76.4 mmol) inmethanol (250 mL) and H₂O (50 mL) was added Oxone® (153 g, 250 mmol) andthe solution was stirred for 20 hours at ambient temperature. The excessOxone® was removed by filtration and the filtrate was concentrated invacuo. The residue was partitioned between ethyl acetate and H₂O and theorganic layer was washed with saturated NaCl and dried over MgSO₄.Concentration in vacuo provided the sulfone as a white solid (18.3 g,96%).

Part C: To a solution of the sulfone of part B (18.3 g, 71.0 mmol) inmethanol (250 mL) was added thionyl chloride (11.0 mL, 150 mmol) and thesolution was heated at reflux for 3 hours. The solution was thereaftercooled and was stirred at ambient temperature for 18 hours. The solutionwas concentrated in vacuo and the residue was partitioned between ethylacetate and saturated NaHCO₃. The aqueous solution was extracted oncewith ethyl acetate and the organic layers were combined and washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided themethyl ester as a tan oil (16.0 g, 80%).

Part D: To a solution of 4-methylmorpholine N-oxide (14.5 g, 123.9 mmol)in acetone/H₂O (8:1, 150 mL) was added osmium tetroxide (2.5 wt. % in2-methyl-2-propanol) followed by the methyl ester of part C (16.0 g,61.9 mmol) in acetone/H₂O. The solution was stirred for 18 hours atambient temperature. To the reaction was added Na₂SO₃ (8 g) and themixture was stirred for 30 minutes followed by concentration in vacuo.The residue was partitioned between ethyl acetate and H₂O and theorganic layer was washed with saturated NaCl and dried over MgSO₄.Concentration in vacuo provided the diol as a white solid (16.3 g, 90%).

Part E: To a solution of thiophenol (700 mg, 6.84 mmol) in DMF (10 mL)was added K₂CO₃ (950 mg, 6.84) and the solution was stirred for 30minutes. To this solution was added the diol of part D (1.0 g, 3.42mmol) and the solution was heated to 70° C. for 2 hours and then for 18hours at ambient temperature. The solution was concentrated in vacuo andthe residue was partitioned between ethyl acetate and 1N HCl. Theorganic layer was washed with H₂O and saturated NaCl and dried overMgSO₄. Concentration in vacuo provided a mixture of ester and acid. Thecrude product was dissolved into acetic acid (15 mL) and concentratedHCl (15 mL) and heated at 70° C. for 3 hours. The solution wasconcentrated in vacuo. Reverse phase chromatography (acetonitrile/H₂O)provided the acid as a white solid (740 mg, 57%).

Part F: To a solution of the acid of part E (740 mg, 2.01 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (330 mg, 2.41 mmol),4-methymorpholine (0.70 mL, 6.03 mmol), 50% aqueous hydroxylamine (2.4mL, 40.2 mmol) and EDC (420 mg, 2.21 mmol). After stirring for 1 hourand standing for 72 hours the solution was concentrated in vacuo.Reverse phase chromatography (acetonitrile/H₂O) followed bycrystallization (acetone/ethanol) providedN,2-dihydroxy-2-(hydroxymethyl)-3-[[4-(phenylthio)-phenyl]sulfonyl]propanamideas white crystals (300 mg, 33%). HPLC purity: 98.7%. HRMS calculated forC₁₆H₁₇NO₆S₂: 384.0576, found 384.0578.

EXAMPLE 14N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]pentylbenzamide

Part A: To a solution of 4-nitrothiophenol (80%, 15.518 g, 92.9 mmol) inmethanol (200 mL) was added triethylamine (14.6 mL, 105 mmol) followedby chloroacetone (8.4 mL,105 mmol). The solution stirred for 1 hour atambient temperature. The solution was concentrated in vacuo and theresidue was dissolved into ethyl acetate and washed with 5% KHSO₄,saturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Chromatography (ethyl acetate/hexanes) provided the sulfide as an oil(16.6 g, 85%).

Part B: To a solution of the sulfide of part A (16.6 g, 78.4 mmol) indichloromethane (150 mL) cooled to 4° C. was added trimethylsilylcyanide (8.56 g, 86.3 mmol) and zinc iodide (1.8 g). The solution wasstirred for 1 hour at 4° C. and for 18 hours at ambient temperature. Thesolution was partitioned between ethyl acetate and H₂O and washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe protected cyanohydrin as a yellow oil (23.7 g).

Part C: To a solution of the cyanohydrin of part B (23.7 g) in aceticacid (100 mL) was added 12N HCl and the solution was heated at refluxfor 17 hours. After concentration in vacuo, trituration of the residuewith ethyl ether provided the acid as a white solid (15.2 g, 75%, 2steps).

Part D: To a solution of the acid of part C (15.2 g, 59 mmol) inmethanol (270 mL) and H₂O (30 mL) was added Oxone® (112.4 g, 183 mmol)and the solution was stirred for 18 hours at ambient temperature. Thesolution was filtered to remove the insoluble salts and the filtrate wasconcentrated in vacuo. The residue was dissolved into ethyl acetate andwashed with H₂O and dried over Na₂SO₄. Concentration in vacuo providedthe sulfone as a solid (12.6 g, 74%).

Part E: To a solution of the sulfone of part D (12.6 g, 43.6 mmol) inmethanol (200 mL) cooled to 0° C. was added thionyl chloride (6.35 mL,87.1 mmol) dropwise. The solution was heated at reflux for 1 hour. Thesolution was cooled and concentrated in vacuo. The residue was dissolvedinto ethyl acetate and washed with H₂O, and saturated NaCO₃, and driedover Na₂SO₄. Concentration in vacuo provided the methyl ester as a beigesolid (12.7 g, 96%).

Part F: To a solution of the methyl ester of part E (12.6 g, 41.5 mmol)in THF (250 mL) under H2 was added wet 10% Pd/C. The solution wasstirred at ambient temperature for 18 hours. The mixture was filteredthrough a Celite pad and the filtrate was concentrated in vacuo toprovide the aniline compound as an off-white solid (11.1 g, 98%).

Part G: To a suspension of the aniline compound of part F (100 mg, 0.37mmol) in dichloromethane (8 mL) was added pyridine (0.044 mL, 0.55 mmol)followed by 4-pentylbenzoyl chloride (0.093 mL, 0.44 mmol). The mixturewas heated to 60° C. for 1 hour. To the solution was added polyamineresin (0.368 g, 1.1 mmol, 2.98 meq/g loading) and heating the solutionwas continued at 60° C. for 1 hour. The mixture was filtered andconcentrated in vacuo to provide the amide as a white solid (167 mg,quantitative yield).

Part H: To a solution of the amide of part G (163 mg, 0.36 mmol) in THF(4 mL) and methanol (4 mL) was added 50% aqueous hydroxylamine (0.60 mL,10.2 mmol). The solution was stirred for 96 hours at ambient temperatureand for 24 hours at 40° C. The solution was concentrated and redissolvedinto THF (1.5 mL) and 50% aqueous hydroxylamine (1.5 mL). The solutionwas stirred for 24 hours and then concentrated. The residue waspartitioned between ethyl acetate and H₂O, and the organic layer waswashed with H₂O and saturated NaCl, and then dried over Na₂SO₄. Reversephase chromatography (acetonitrile/H₂O) provided the hydroxamate,N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-pentylbenzamide,as a pink solid (103 mg, 63%). MS(CI) MH⁺ calculated for C₂₂H₂₈N₂O₆S:449, found: 449.

EXAMPLE 15N,2-dihydroxy-2-methyl-3-[[4-[((phenylamino)carbonyl)amino]phenyl]sulfonyl]propanamide

Part A: To a solution of the aniline compound of Example 14, part F (500mg, 1.83 mmol) in dichloromethane (10 mL) was added phenyl isocyanate(436 mg, 3.66 mmol) and the solution was stirred for 20 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate and washed with H₂O and saturated NaCl anddried over Na₂SO₄. Concentration in vacuo provided the urea methyl esteras an oil (392 mg, 55%).

Part B: To a solution of the urea methyl ester of part A (392 mg, 1.0mmol) was added 50% aqueous hydroxylamine (3.0 mL) and the solutionstirred for 96 hours. The solution was diluted with ethyl acetate andwashed with H₂O and saturated NaCl, and then dried over Na₂SO₄. Reversephase chromatography (acetonitrile/H₂O) providedN,2-dihydroxy-2-methyl-3-[[4-[[(phenylamino)-carbonyl]amino]phenyl]sulfonyl]-propanamideas a pink solid (77 mg, 20%). MS(CI) MH⁺ calculated for C₁₇H₁₉N₃O₆S:394, found: 394.

EXAMPLE 16N-(4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in 1,2-dichloroethane (20 mL) was added pyridine (0.22 mL, 2.7mmol) followed by benzoyl chloride (0.25 mL, 2.2 mmol). The solutionstirred at ambient temperature for 1 hour followed by the addition ofpolyamine resin (3.0 meq/g loading, 1.5 g, 4.5 mmol) and the stirringwas continued for 1 hour. The mixture was filtered and the filtrate wasconcentrated in vacuo to provide the amide methyl ester as an off-whitesolid (688 mg, 99%).

Part B: To a solution of the amide methyl ester of part A (674 mg, 1.79mmol) in THF (15 ml) was added 50% aqueous hydroxylamine (15 mL) and wasstirred for 72 hours. The solution was concentrated and the residue wasextracted with ethyl acetate and washed with saturated NaCl, and thendried over Na₂SO₄. Trituration with ethyl acetate and ethyl etherprovidedN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamideas a white solid (328 mg, 48%). MS(CI) MH⁺ calculated for C₁₇H₁₈N₂O₆S:379, found: 379.

EXAMPLE 17N-[4[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbutanamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in 1,2-dichloroethane (20 mL) was added pyridine (0.22 mL, 2.7mmol) followed by isovaleryl chloride (0.27 mL, 2.2 mmol). The solutionstirred at ambient temperature for 1.5 hours followed by the addition ofpolyamine resin (3.0 meq/g loading, 1.5 g, 4.5 mmol) and the stirringcontinued for 1 hour. The mixture was filtered and the filtrate wasconcentrated in vacuo to provide the methyl ester amide as a yellow oil(746 mg, quantitative yield).

Part B: To a solution of the methyl ester amide of part A (736 mg, 1.83mmol) in THF (10 mL) was added 50% aqueous hydroxylamine (10 mL), andthe solution was stirred for 96 hours. The solution was concentrated andthe residue was extracted with ethyl acetate, washed with saturatedNaCl, and then dried over Na₂SO₄. Reverse phase chromatography(acetonitrile/H₂O) providedN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbutanamideas a pink solid (247 mg, 38t). MS(CI) MH⁺ calculated for C₁₅H₂₂N₂O₆S:359, found: 359.

EXAMPLE 184-chloro-N-[4-[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-benzamide

Part A: To a solution of the aniline of Example 14, part F (300 mg, 1.10mmol) in 1,2-dichloroethane (10 mL) was added pyridine (0.133 mL, 1.65mmol) followed by 4-chlorobenzoyl chloride (0.17 mL, 1.3 mmol). Thesolution stirred at ambient temperature for 1 hour. The resultingprecipitate was triturated with ethyl ether and collected to provide theamide methyl ester as a white solid (368 mg, 81%).

Part B: To a solution of the amide methyl ester of part A (368 mg, 0.89mmol) in THF (2 mL) and methanol (4 mL) was added 50 aqueoushydroxylamine (3 mL) and was stirred for 96 hours. The solution wasconcentrated and the residue was extracted with ethyl acetate and washedwith saturated NaCl and dried over Na₂SO₄. Trituration with ethylacetate provided4-chloro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-benzamideas a white solid (126 mg, 34%). MS(CI) MH⁺ calculated for C₁₇H₁₇N₂O₆SCl:430, found: 430.

EXAMPLE 19N,2-dihydroxy-2-methyl-3-[[4-[[[(2-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in 1,2-dichloroethane (15 mL) was added o-tolyl isocyanate (0.354mL, 2.74 mmol). The solution was heated to 60° C. for 15 hours followedby the addition of polyamine resin (3.0 meq/g loading, 1.00 g, 3.00mmol) and continued heating for 7 hours. The mixture was filtered andthe filtrate was concentrated. Chromatography (ethyl acetate/hexane)provided the urea methyl ester as a pink solid (496 mg, 67%).

Part B: To a solution of the urea methyl ester of part A (496 mg, 1.22mmol) in THF (12 mL) was added potassium trimethylsilanolate (188 mg,1.46 mmol) and was stirred for 20 hours at ambient temperature. Thesolution was cooled to zero degrees C., diluted with H₂O and acidifiedwith 1N HCl (1.5 mL). The THF was removed. The aqueous layer wasextracted with ethyl acetate, and the organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe acid as a yellow solid (480 mg, quantitative yield).

Part C: To a solution of the acid of part B (480 mg, 1.22 mmol) in DMF(12 mL) was added N-hydroxy-benzotriazole (181 mg, 1.34 mmol) and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (257 mg,1.34 mmol). After 1 hour of stirring at ambient temperature 50% aqueoushydroxylamine (0.216 mL, 3.66 mmol) and 4-methylmorpholine (0.54 mL, 4.9mmol) were added. After 30 minutes the DMF was removed and the residuewas partitioned between ethyl acetate and H₂O. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Reverse phasechromatography providedN,2-dihydroxy-2-methyl-3-[[4-[[[(2-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamideas a pink solid (39 mg, 8*). MS(CI) MH⁺ calculated for C₁₈H₂₁N₃O₆S: 408,found 408.

EXAMPLE 20N,2-dihydroxy-2-methyl-3-[[4-[[[(3-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in 1,2-dichloroethane (15 mL) was added m-tolyl isocyanate (0.353mL, 2.74 mmol). The solution was heated to 60° C. for is hours followedby the addition of polyamine resin (3.0 meq/g loading, 1.00 g, 3.00mmol) and continued heating for 7 hours. The mixture was filtered andthe filtrate was concentrated. Chromatography (ethyl acetate/hexane)provided the urea methyl ester as a pale yellow oil (346 mg, 47%).

Part B: To a solution of the urea methyl ester of part A (346 mg, 0.851mmol) in THP (10 mL) was added potassium trimethylsilanolate (131 mg,1.02 mmol) and was stirred for 18 hours at ambient temperature. Thesolution was cooled to zero degrees C., diluted with H₂O and acidifiedwith 1N HCl. The THF was removed. The aqueous layer was extracted withethyl acetate and the organic layer was washed with saturated NaCl anddried over Na₂SO₄. Concentration in vacuo provided the acid as a pinksolid (330 mg, 99%).

Part C: To a solution of the acid of part B (330 mg, 0.841 mmol) in DMF(8 mL) was added N-hydroxy-benzotriazole (125 mg, 0.925 mmol) and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (177 mg,0.925 mmol). After 1 hour of stirring at ambient temperature 50% aqueoushydroxylamine (0.149 mL, 2.52 mmol) and 4-methylmorpholine (0.37 mL, 3.7mmol) were S added. After 30 minutes the DMF was removed and the residuewas partitioned between ethyl acetate and H₂O. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Reverse phasechromatography providedN,2-dihydroxy-2-methyl-3-[[4-[[[(3-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamideas a white solid (265 mg, 77%). MS(CI) MH⁺ calculated for C₁₈H₂₁ ₂N₃O₆S:408, found: 408.

EXAMPLE 21N,2-dihydroxy-2-methyl-3-[[4-[[[(4-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in THF (15 mL) was added p-tolyl isocyanate (0.461 mL; 3.66 mmol).The solution was stirred at ambient temperature for 72 hours. Thesolution was then diluted with dichloromethane (50 mL) and polyamineresin (3.0 meq/g loading, 2.50 g, 7.50 mmol) was added and the mixturestirred for 4 hours. The mixture was filtered and the filtrate wasconcentrated. Chromatography (ethyl acetate/hexane) provided the ureamethyl ester as a white solid (554 mg, 74%).

Part B: To a solution of the urea methyl ester of part A (554 mg, 1.36mmol) in THF (13 mL) was added potassium trimethylsilanolate (210 mg,1.64 mmol) and the solution was stirred for 18 hours at ambienttemperature. The solution was cooled to zero degrees C., diluted withH₂O and acidified with1N HCl. The THF was removed. The aqueous layer wasextracted with ethyl acetate and the organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo providedthe acid as an off-white solid (530 mg, 99%).

Part C: To a solution of the acid of part B (500 mg, 1.27 mmol) in DMF(13 mL) was added N-hydroxy-benzotriazole (189 mg, 1.40 mmol) andl-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (268 mg,1.40 mmol). After 1 hour of stirring at ambient temperature 50% aqueoushydroxylamine (0.282 mL, 3.81 mmol) and 4-methylmorpholine (0.56 mL, 5.1mmol) were added. After 30 minutes the DMF was removed and the residuewas partitioned between ethyl acetate and H₂O. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Reverse phasechromatography providedN,2-dihydroxy-2-methyl-3-[[4-[[[(4-methylphenyl)amino]carbonyl]amino]phenyl]sulfonyl]propanamideas an off-white solid (202 mg, 39%). MS(CI) MH⁺ calculated forC₁₈H₂₁N₃O₆S: 408, found 408.

EXAMPLE 226-chloro-N-(4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-pyridinecarboxamide

Part A: To a solution of the aniline of Example 14, part F (500 mg, 1.83mmol) in 1,2-dichloroethane (10 mL) was added pyridine (0.22 mL, 2.7mmol) followed by 6-chloronicotinyl chloride (383 mg, 2.2 mmol). Thesolution stirred at ambient temperature for 1 hour followed by theaddition of polyamine resin (3.0 meq/g loading, 1.5 g, 4.5 mmol) and thestirring was continued for 1 hour. The mixture was filtered and thefiltrate was concentrated in vacuo to provide the amide methyl ester asan off-white solid (750 mg, 99%).

Part B: To a solution of the amide methyl ester of part A (750 mg, 1.82mmol) in THF (10 mL) was added 50% aqueous hydroxylamine (3 mL) and wasstirred for 96 hours. The solution was concentrated, the residue wasextracted with ethyl acetate, washed with saturated NaCl and dried overNa₂SO₄. Reverse phase chromatography (acetonitrile/H₂O) provided6-chloro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-pyridinecarboxamideas a white solid (29 mg, 4%). MS(CI) M−H calculated for C₁₆H₁₆N₃O₆SCl:412, found: 412.

EXAMPLE 23N-[4-[[2-hydroxy-3-(hydroxyamino)-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF(200 mL) was added K₂CO₃ (33.3 g, 240.96 mmol) and 4-aminothiophenol(11.60 g, 92.66 mmol). The solution was stirred for 20 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into H₂O and acidified with 6N HCl to pH=2.5. The resultingprecipitate was collected by vacuum filtration and dried providing theacid sulfide as an off-white solid (12.4 9 g, 72%).

Part B: To a solution of the acid sulfide of part A (11.88 g, 55.71mmol) in methanol (200 mL) cooled to zero degrees C. was added thionylchloride (12.2 mL, 167.13 mmol). The solution was heated at reflux for 2hours followed by concentration in vacuo. The residue was dissolved intosaturated NaHCO₃ and extracted with ethyl acetate. The organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Concentration in vacuoprovided the methyl ester as a tan solid (11.47 g, 91%).

Part C: To a suspension of the methyl ester of part B (10.00 g, 44.0mmol) in dichloromethane (100 mL) was added pyridine (5.34 mL, 66.00mmol) and benzoyl chloride (5.62 mL, 48.4 mmol). The solution wasstirred at ambient temperature for 20 hours. The solution wasconcentrated in vacuo. The residue was partitioned between ethyl acetateand H₂O, and the organic layer was washed with H₂O and saturated NaCl.Concentration in vacuo provided the amide sulfide as an off-white solid(14.56 g, quantitative yield).

Part D: To a solution of the amide sulfide of part C (3.00 g, 9.05 mmol)in THF (100 mL) and H₂O (mL) was added Oxone® (10.0 g, 16.3 mmol). Thesolution stirred at zero degrees C. for 2 hours. The mixture wasfiltered and the filtrate was concentrated to one-third volume. Thissolution was diluted with ethyl acetate, washed with H₂O and saturatedNaCl, and then dried over Na₂SO₄. Chromatography (ethyl acetate/hexane)provided the sulfone methyl ester as an off-white solid (2.68 g, 81%).

Part E: To a solution of the sulfone methyl ester of part D (500 mg,1.38 mmol) in THF (6 mL) was added 50% aqueous hydroxylamine (6 mL). Thesolution was stirred at ambient temperature for 8 hours. Triturationwith THF providedN-[4-[[2-hydroxy-3-(hydroxyamino)-3-oxopropyl]sulfonyl]phenyl]benzamideas an off-white solid (393 mg, 78%). MS(CI) MH⁺ calculated forC₁₆H₁₆N₂O₆S: 365, found: 365.

EXAMPLE 244-(heptyloxy)-N-[4-[[2-hydroxy-3-(hydroxyamino)-2methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (532mg, 1.95 mmol) in THF (15 mL) was added triethylamine (1.09 mL, 7.8mmol) and 4-heptyloxybenzoyl chloride (502 mg, 1.95 mmol) and thesolution was refluxed for 1.5 hours. Chromatography (ethylacetate/hexane) provided the amide methyl ester (605 mg, 63w).

Part B: To a solution of the amide methyl ester of part A (500 mg, 1.02mmol) in THF (10 mL) and methanol (10 mL) was added 50% aqueoushydroxylamine (12 mL) and the solution stirred for 11 days at ambienttemperature. The solvent was concentrated in vacuo. The residue wasdissolved into ethyl acetate, washed with H₂O and dried over Na₂SO₄.Crystallization (hexane) provided4-(heptyloxy)-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-benzamideas a white solid (215 mg, 43%). HRMS (MH⁺) calculated for C₂₄H₃₂N₂O₇S:493.2008, found: 493.2027.

EXAMPLE 254-butoxy-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (560mg, 2.05 mmol) in THF (15 mL) was added triethylamine (1.14 mL, 8.2mmol) and 4-butoxybenzoyl chloride (654 mg, 3.075 mmol) and the solutionwas refluxed for 5 hours. The solution was concentrated in vacuo, andtrituration with ethyl ether provided the amide methyl ester as whitesolid (407 mg, 43%).

Part B: To a solution of the amide methyl ester of part A (400 mg, 0.89mmol) in THF (10 mL) was added 50% aqueous hydroxylamine (10 mL) and thesolution was stirred at ambient temperature for 72 hours. The solutionwas concentrated in vacuo. The residue was partitioned between ethylacetate and H₂O, and the organic layer was dried over Na₂SO₄.Concentration in vacuo provided4-butoxy-N-(4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-benzamideas a white solid (335 mg, 84%). HRMS (ME⁺) calculated for C₂₁H₂₆N₂O₇S:451.1539, found: 451.1540.

EXAMPLE 26N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]4-propylbenzamide

Part A: To a solution of the aniline compound of Example 14, part F (530mg, 1.94 mmol) in THF (10 mL) was added triethylamine (1.08 mL, 7.76mmol) followed by 4-propylbenzoyl chloride (532 mg, 2.91 mmol) and thesolution was heated at reflux for 3 hours. The solution was concentratedin vacuo. The residue was dissolved into ethyl acetate, washed with H₂Oand dried over Na₂SO₄. Recrystallization (ethyl acetate/hexane) providedthe amide methyl ester as white crystals (570 mg, 70%).

Part B: To a solution of the amide methyl ester of part A (560 mg, 1.3mmol) in THF (10 mL) was added 50% hydroxylamine (10 mL) and thesolution was stirred for 7 days. The solution was concentrated in vacuoand the residue was partitioned between ethyl acetate and H₂O. Theorganic was dried over Na₂SO₄. Concentration in vacuo providedN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl)-4-propylbenzamideas a white solid (438 mg, 80%). HRMS (MH⁺) calculated for C₂₀H₂₄N₂O₆S:421.1433, found: 421.1396.

EXAMPLE 27N-(4-[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]-phenyl]3-methoxybenzamide

Part A: To a solution of the aniline compound of Example 14, part F (563mg, 2.06 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.19mmol) followed by m-anisoyl chloride (0.434 mL, 3.09 mmol) and thesolution was heated at reflux for 3 hours. The solution was concentratedin vacuo. The residue was dissolved into ethyl acetate, washed with H₂Oand dried over Na₂SO₄. Recrystallization (ethyl acetate/hexane) providedthe amide methyl ester as white crystals (539 mg, 64%).

Part B: To a solution of the amide methyl ester of part A (530 mg, 1.3mmol) in THF (10 mL) was added 50% hydroxylamine (10 mL) and thesolution was stirred for 7 days. The solution was concentrated in vacuoand the residue was partitioned between ethyl acetate and H₂O. Reversephase chromatography (acetonitrile/H₂O) providedN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]-3-methoxybenzamideas a white solid (190 mg, 36%). HRMS (MN⁺) calculated forC_(a18)H₂₀N₂O₇S: 409.1069, found: 409.1093.

EXAMPLE 28 4-butyl-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (573mg, 2.10 mmol) in THF (10 mL) was added triethylamine (1.3 mL, 9.3 mmol)followed by 4-butylbenzoylchloride (619 mg, 3.15 mmol) and the solutionwas heated at reflux for 4.5 hours. The solution was concentrated invacuo. The residue was dissolved into ethyl acetate, washed with H₂O anddried over Na₂SO₄. Recrystallization (ethyl acetate/hexane) provided theamide methyl ester as a white solid (682 mg, 75%).

Part B: To a solution of the amide methyl ester of part A (682 mg, 1.6mmol) in THF (10 mL) was added 50% hydroxylamine (10 mL) and thesolution was stirred for 10 days. The solution was concentrated invacuo, and the residue was partitioned between ethyl acetate and H₂.Concentration in vacuo provided4-butyl-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]benzamideas a white solid (522 mg, 75%). HRMS (MN⁺) calculated for C₂₁H₂₆N₂O₆S:435.1590, found: 435.1577.

EXAMPLE 293-fluoro-N-[4-[12-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (566mg, 2.07 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol)followed by 3-fluorobenzoyl chloride (490 mg, 3.1 mmol) and the solutionwas heated at reflux for 4.5 hours. The solution was concentrated invacuo. The residue was dissolved into ethyl acetate, washed with H₂O anddried over Na₂SO₄. Chromatography (ethyl acetate/hexane) provided theamide methyl ester as a white solid (460 mg, 56%).

Part B: To a solution of the amide methyl ester of part A (400 mg, 1.0mmol) in THF (20 mL) and methanol (5 mL) was added 50% hydroxylamine (20mL) and the solution was stirred for 20 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. Concentration in vacuo provided3-fluoro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamideas a white solid (363 mg, 91%). HRMS (MH⁺) calculated for C₁₇H₁₇N₂O₆SF:397.0870, found: 397.0864.

EXAMPLE 30N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbenzamide

Part A: To a solution of the aniline compound of Example 14, part F (537mg,1.97 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol)followed by m-toluoyl chloride (0.39 mL, 2.9 mmol) and the solution washeated at ref lux for 5 hours. The solution was concentrated in vacuo.The residue was dissolved into ethyl acetate, washed with H₂O and driedover Na₂SO₄. Chromatography (ethyl acetate/hexane) provided the amidemethyl ester as an oil (550 mg, 71%).

Part B: To a solution of the amide methyl ester of part A (500 mg, 1.3mmol) in THF (10 mL) and methanol (5 mL) was added 50% hydroxylamine (20mL) and the solution was stirred for 25 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. Concentration in vacuo3 providedN-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbenzamideas a white solid (352 mg, 70t). HRMS (MH⁺) calculated for C₁₈H₂₀N₂O₆S:393.1120, found: 5 393.1127.

EXAMPLE 313-chloro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (525mg, 1.92 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol)followed by 3-chlorobenzoyl chloride (0.322 mL, 2.88 mmol) and thesolution was heated at reflux for 5 hours. The solution was concentratedin vacuo. The residue was dissolved into ethyl acetate, washed with H₂Oand dried over Na₂SO₄. Crystallization (ethyl acetate/hexane) providedthe amide methyl ester as a white solid (230 mg, 29%).

Part B: To a solution of the amide methyl ester of part A (230 mg, 0.56mmol) in THF (5 mL)and 25 methanol (5 mL) was added 50% hydroxylamine(10 mL) and the solution was stirred for 48 hours. The solution wasconcentrated in vacuo and t he residue was partitioned between ethylacetate and H₂O. Concentration in vacuo provided3-chloro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamideas a white solid (160 mg, 70%). HRMS (MH⁺) calculated for C₁₇H₁₇N₂O₆S:430.0840, found: 430.0864.

EXAMPLE 323,4-difluoro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (531mg, 1.94 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol)followed by 3,4-difluorobenzoyl chloride (0.367 mL, 2.92 mmol) and thesolution was heated at reflux for 18 hours. The solution wasconcentrated in vacuo. The residue was dissolved into ethyl acetate,washed with H₂O and dried over Na₂SO₄ Chromatography (ethylacetate/hexane) provided the amide methyl ester as a white solid (360mg, 45%).

Part B: To a solution of the amide methyl ester of part A (359 mg, 0.87mmol) in THF (10 mL) and methanol (5 mL) was added 50% hydroxylamine (15mL) and the solution was stirred for 20 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. Reverse phase chromatography (acetonitrile/H₂O)provided3,4-difluoro-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamideas a white solid (165 mg, 46%). HRMS (MH⁺) calculated for C₁₇H₁₆N₂O₆SF₂:415.0775, found: 415.0778.

EXAMPLE 33N-(4-[[2-hydroxy-3-hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]-3-nitrobenzamide

Part A: To a solution of the aniline compound of Example 17, part F (750mg, 2.75 mmol) in THF (30 mL) was added triethylamine (1.32 mL, 9.6mmol) followed by 3-nitrobenzoyl chloride (765 mg, 4.12 mmol) and thesolution was heated at reflux for 6 hours. The solution was concentratedin vacuo. The residue was dissolved into ethyl acetate, washed with H₂Oand dried over Na₂SO₄. Chromatography (ethyl acetate/hexane) providedthe amide methyl ester as a white solid (109 mg, 9%).

Part B: To a solution of the amide methyl ester of part A (100 mg, 0.24mmol) in methanol (20 mL) was added 50% hydroxylamine (20 mL) and thesolution was stirred for 20 hours. The solution was concentrated invacuo and the residue was partitioned between ethyl acetate and H₂O.Concentration in vacuo providedN-[4-[[2-hydroxy-3-hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]-3-nitrobenzamideas a white solid (43 mg, 43%). HRMS (MH⁺) calculated for C₁₇H₁₇N₃O₈S:424.0815, found: 424.0827.

EXAMPLE 34 3-[(4-hydroxybutyl)amino]-N[4-[[2-hydroxy-3-hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part (789mg, 2.9 mmol) in THF (20 mL) was added triethylamine (3.0 mL, 21.6 mmol)followed by 3-nitrobenzoyl chloride (2-0 g, 10.8 mmol) and the solutionwas heated at reflux for 3.5 hours. The solution was concentrated invacuo. The residue was dissolved into ethyl acetate, washed with H₂O anddried over Na₂SO₄. Chromatography (ethyl acetate/hexane/methanolprovided the nitro amide methyl ester as a white solid (313 mg, 25%).

Part B: To a solution of 4% Pd/C (130 mg) in methanol under anatmosphere of N₂ was added the nitro amide methyl ester compound of partA (508 mg, 1.2 mmol) in THF (20 mL). The atmosphere was purged 5 timeswith H₂ at 50 psi. The solution was then filtered through Celite® toremove the catalyst. The filtrate was purified by chromatography (ethylacetate/methanol) to provide the THF adduct amine methyl ester (240 mg,43%).

Part C: To a solution of the THF adduct amine methyl ester of part B(230 mg,0.49 mmol) in methanol (20 mL) was added 50% hydroxylamine (20mL) and the solution was stirred for 20 hours. The solution wasconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. Concentration in vacuo provided3-[(4-hydroxybutyl)amino]-N[4-[[2-hydroxy-3-hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-benzamideas a white solid (105 mg, 46%). HRMS (MH⁺) calculated for C₂₁H₂₇N₃O₇S:466.1648, found: 466.1643.

EXAMPLE 35 3-amino-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide

Part A: To a solution of the aniline compound of Example 14, part F (789mg, 2.9 mmol) in THF (20 mL) was added triethylamine (3.0 mL, 21.6 mmol)followed by 3-nitrobenzoyl chloride (2.0 g, 10.8 mmol) and the solutionwas heated at reflux for 3.5 hours. The solution was concentrated invacuo. The residue was dissolved into ethyl acetate, washed with H₂O anddried over Na₂SO₄. Chromatography (ethyl acetate/hexane/methanol)provided the nitro amide methyl ester as a white solid (313 mg, 25%).

Part B: To a solution of 4% Pd/C (200 mg) in methanol under anatmosphere of N₂ was added the nitro amide methyl ester compound of partA (600 mg, 1.4 mmol) in methanol (80 mL). The atmosphere was purged 5times with H₂ at 50 psi. The solution was stirred overnight. Thesolution was then filtered through Celite® to remove the catalyst. Thefiltrate was purified by chromatography (ethyl acetate/methanol) toprovide the aniline methyl ester (543 mg, 99%).

Part C: To a solution of the aniline methyl ester of part B (540 mg,1.38 mmol) in methanol (5 mL) was added 50% hydroxylamine (5 mL) and thesolution was stirred for 24 hours. The solution was concentrated invacuo. Trituration (ethyl acetate/ethyl ether) provided3-amino-N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]benzamideas a white solid (434 mg, 80%). HRMS (MH⁺) calculated for C₁₇H₁₉N₃O₆S:394.1073, found: 394.1070.

EXAMPLE 36 In Vitro Metalloprotease Inhibition

The compounds prepared in the manner described in Examples 1 to 9 wereassayed for activity by an in vitro assay. Following the procedures ofKnight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

More specifically, recombinant human MMP-13 and MMP-1 enzymes wereprepared in laboratories of the assignee. MMP-13 was expressed inbaculovirus as a proenzyme, and purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay. MMP-1 expressed in transfectedHT-1080 cells was provided by Dr. Howard Welgus of WashingtonUniversity, St. Louis, Mo. The enzyme was also activated using APMA andwas then purified over a hydroxamic acid column.

The enzyme substrate is a methoxycoumarin-containing polypeptide havingthe following sequence:

MCA-ProLeuGlyLeuDpaAlaArgNH², wherein MCA is methoxycoumarin and Dpa is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem as product M-1895.

The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mMCaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pHvalue of 7.5. Assays were carried out at room temperature, and dimethylsulfoxide (DMSO) at a final concentration of 1 percent was used todissolve compound.

The assayed inhibitor compound in DMSO/buffer solution was compared toan equal amount of DMSO/buffer with no inhibitor as control usingMicrofluor™ White Plates (Dynatech). The inhibitor or control solutionwas maintained in the plate for 10 minutes and the substrate was addedto provide a final concentration of 4 μM.

In the absence of inhibitor activity, a fluorogenic peptide was cleavedat the gly-leu peptide bond, separating the highly fluorogenic peptidefrom a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set forth in the Inhibition Table (Table 51) below, reported interms of IC₅₀.

TABLE 51 IC₅₀ VALUES (in nM) Example MMP-13 MMP-1 MMP-2 MMP-3 MMP-8MMP-9  1 1.1 1100 0.5 30 2.5 4.8 1A(S) 0.75 1005 0.39 1.7 1B(R)21.5 >10,000 11.0 328  2 1.2 470 1.0 44 4.1 7  3 3 6000 1.0 166 4 20  40.4 9000 0.4 48.5 4.5 12.4  5 1.3 >10,000 2.4 26.8 2.5 3.4  6 30 800014.8  7 2.1 >10,000 2.0 51.8 4.0 13.0  8 200 >10,000  9 0.2 3000 0.416.0 10 1.0 4000 0.4 18.0 11 5.0 7000 7 66.0 12 3.7 >10,000 2.0 175 135.0 >10,000 2.3 70.0 14 0.5 >10,000 <0.1 15 3200 >10,000 87 16110 >10,000 0.8 1160 17 900 >10,000 400 18 13 >10,000 0.5 1910,000 >10,000 2600 20 6600 >10,000 300 21 3600 >10,000 34 22280 >10,000 6.7 23 220 >10,000 2.8 1330 24 <0.1 >10,000 <0.1 251.2 >10,000 0.2 26 1.2 >10,000 0.1 27 666 >10,000 10.0 28 0.8 >10,000<0.1 29 80 >10,000 1.8 30 316 >10,000 20 31 600 >10,000 37.2 3280 >10,000 1.6 33 1600 >10,000 50 34 1600 >10,000 32.7 35 290 >10,0006.7

EXAMPLE 37 In Vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, Jul.1996, Vol. 37, No. 8.

In this assay, uniformly sized Hydron™ pellets containing bFGF andsucralfate were prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets were formed bymaking a suspension of 20 μL sterile saline containing 10 pg recombinantbFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol.The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh were separated to release thepellets.

The corneal pocket was made by anesthetizing a 7 week old C57Bl/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length was performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket was dissected toward the temporallimbus. The pocket was extended to within 1.0 mm of the temporal limbus.A single pellet was placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet was then advanced to thetemporal end of the pocket. Antibiotic ointment was then applied to theeye.

Mice were dosed on a daily basis for the duration of the assay. Dosingof the animals was based on bioavailability and overall potency of thecompound. An exemplary dose is 50 mg/kg bid, po. Neovascularization ofthe corneal stroma begins at about day three and was permitted tocontinue under the influence of the assayed compound until day five. Atday five, the degree of angiogenic inhibition was scored by viewing theneovascular progression with a slit lamp microscope.

The mice were anesthetized and the studied eye was once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet was measured. In addition, thecontiguous circumferential zone of neovascularization was measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis was calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

The studied mice were thereafter compared to control mice and thedifference in the area of neovascularization was recorded. Acontemplated compound typically exhibits about 25 to about 75 percentinhibition, whereas the vehicle control exhibits zero percentinhibition. The results of this assay for several inhibitor compoundsare shown in Table 52, below.

TABLE 52 Percentage of Example Control 1 51.9 1A(S) 62.7 1B(R) 49.3 253.4 3 77.4 4 65.2 5 57.8 9 61.1 16  41.6

From the foregoing, it will be observed that numerous modifications andvariations can be carried out without departing from the true spirit andscope of the novel concepts of the present invention. It is to beunderstand that no limitation with respect to the specific examplepresented is intended or should be inferred. The disclosure is intendedto cover by the appended claims all such modifications as fall withinthe scope of the claims.

What is claimed is:
 1. A compound corresponding to Formula I:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; R¹ is phenylsubstituted with R³; and R³ is selected from the group consisting ofphenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido,benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo,heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarbyloxyhydrocarbyl,arylcarbonylhydrocarbyl, arybazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio,wherein: such substituent itself optionally is substituted with one ormore substituents selected from the group consisting of halogen,hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl,trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy,arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy,heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, N-monosubstituted aminohydrocarbyl,and N,N-disubstituted aminohydrocarbyl group, wherein: thesubstituent(s) on the monosubstituted or disubstituted aminohydrocarbylnitrogen is/are selected from the group consisting of hydrocarbyl, aryl,arlhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the substituents on thedisubstituted aminohydrocarbyl nitrogen, together with the disubstitutedaminohydrocarbyl nitrogen itself, form a 5- to 8-membered heterocyclicor heteroaryl ring group.
 2. The compound according to claim 1 whereinthe compound corresponds to:


3. The compound according to claim 2 wherein R³ is selected from thegroup consisting of a phenyl group, a phenoxy, a thiophenoxy, ananilino, a phenylazo, a phenylureido, a benzamido, a nicotinamido, anisonicotinamido, a picolinamido, a heterocyclo, hetercyclohydrocarbyl,arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl,heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl,aryloxyhydrocarbyl, hydrocarboylhydrocarbyl,arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl,arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl,arylthiohydrocarbyl, heteroarylthiohydrocarbyl,hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl,arylhydrocarbylthioaryl, arylhydrocarbylamino,heteroarylhydrocarbylamino, and a heteroarylthio group.
 4. The compoundaccording to claim 2 wherein R³ is selected from the group consisting ofphenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido,benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo,heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio,wherein: such substituent is itself substituted by one or moresubstituents selected from the group consisting of a halogen,hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl,trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy,arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy,heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,hetoroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycrabonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhdrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, N-monosubstituted aminohydrocarbyl,and N,N-disubstituted aminohydrocarbyl group, wherein: thesubstituent(s) on the monosubstituted or disubstituted aminohydrocarbylnitrogen is/are selected from the group consisting of hydrocarbyl, aryl,arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the substituents on thedisubstituted aminohydrocarbyl nitrogen, together with the disubstitutedaminohydrocarbyl nitrogen itself, form a 5- to 8-membered heterocyclicor heteroaryl ring group.
 5. A compound according to claim 1, whereinthe compound corresponds to:


6. A compound according to claim 1, wherein the compound corresponds to:


7. A compound according to claim 1, wherein the compound corresponds to:


8. A compound according to claim 1, wherein the compound corresponds to:


9. A compound according to claim 1, wherein the compound corresponds to:


10. A compound according to claim 1, wherein the compound correspondsto:


11. A compound according to claim 1, wherein the compound correspondsto:


12. A compound according to claim 1, wherein the compound correspondsto:


13. A compound according to claim 1, wherein the compound correspondsto:


14. A compound according to claim 1, wherein the compound correspondsto:


15. A compound corresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is selectedfrom the group consisting of a single-ringed cyclohydrocarbyl group, asingle-ringed heteroryclo group, a single-ringed aryl group, asingle-ringed heteroaryl group, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a4-thiopyridyl group, a phenylazo group, a phenylureido group, anicotinamido group, an isonicotinamido group, a picolinamido group, ananilino group, and a benzamido group.
 16. The compound according toclaim 15 wherein R³ is a phenyl, phenoxy, thiophenoxy, phenylazo,benzamido, anilino, nicotinamido, isonicotinamido, picolinamido, orphenylureido group.
 17. A compound corresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is a phenyl,phenoxy, anilino, or thiophenoxy group that is optionally substituted:at the meta- or para-position or both with a moiety that is selectedfrom the group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, aC₁-C₁₀ hydrocarbyl group, a di-C₁-C₉ hydrocarbylamino group, a carboxylC₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbylgroup, and a C₁-C₈-hydrocarbyl carboxamido group, or at the meta- andpara-positions by two methyl groups or by a methylenedioxy, group.
 18. Acompound corresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is benzamido,nicotinamido, isonicotinamido, picolinamido, or phenylureido, wherein:such substituent is optionally substituted at its own meta- orpara-position or both with a moiety selected from the group consistingof a halogen, a nitro, a C₁-C₈ hydrocarbyl, a C₁-C₇ hydrocarbyloxy, anamino, and an amino-C₂-C₄-hydroxyalkyl group.
 19. A compoundcorresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is a phenyl,phenoxy, thiophenoxy, anilino, phenylazo, benzamido, nicotinamido,isonicotinamido, picolinamido, or phenylureido, wherein: suchsubstituent itself optionally is substituted with one or moresubstituents selected from the group consisting of halogen, hydrocarbyl,hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl,trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy,arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy,heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycarbonylhydrocarlyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhdrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, N-monosubstituted aminohydrocarbyl,and N,N-disubstituted aminohydrocarbyl group, wherein: thesubstituent(s) on the monosubstituted or disubstituted aminohydrocarbylnitrogen is/are selected from the group consisting of hydrocarbyl, aryl,arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the substituents on thedisubstituted aminohydrocarbyl nitrogen, together with the disubstitutedaminohydrocarbyl nitrogen itself, form a 5- to 8-membered heterocyclicor heteroaryl ring group.
 20. The compound according to claim 19 whereinsaid R² substituent is methyl, hydroxymethyl, methoxymethyl or(N-morpholino)methyl group.
 21. The compound according to claim 19wherein said compound is an enantiomer whose stereoconfiguration is asshown in the following formula:


22. A compound corresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl C₁-C₄ hydrocarbyloxymethyl,aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl, (N,N-di-C₁-C₃hydrocarbyl)aminomethyl, (N-morpholino)methyl, (N-pyrrolidino)methyl, or(N-thiomorpholino)methyl; and R³ is a phenyl, phenoxy, anilino, orthiophenoxy group that is itself optionally substituted: at the meta orpara position or both with a moiety that is selected from the groupconsisting of a halogen, a C₁-C₉ hydrocarbyloxy group, a C₁-C₁₀hydrocarbyl group, a di-C₁-C₉ hydrocarbylamino group, a carboxyl C₁-C₈hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbylgroup, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl group, and aC₁-C₈ hydrocarbyl carboxamido group, or at the meta- and para-positionsby two methyl groups or by a alkylenedioxy group.
 23. The compoundaccording to claim 22 wherein said R³ is a phenoxy or thiophenoxy groupthat is unsubstituted.
 24. A compound corresponding to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is abenzamido, nicotinamido, isonicotinamido, picolinamido, or phenylureidogroup, wherein: such substituent is substituted at its own meta- orpara-position with a moiety selected from the group consisting of ahalogen, a nitro, a C₁-C₈ hydrocarbyl, a C₁-C₇ hydrocarbyloxy, an amino,and an amino-C₂-C₄-hydroxyalkyl group.
 25. A process for treating a hostanimal having a condition associated with pathological matrixmetalloprotease activity that comprises administering a compound in anMMP enzyme-inhibiting effective amount to a mammalian host having such acondition, wherein the compound corresponds in structure to Formula I:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; R¹ is phenylsubstituted with R³; and R³ is selected from the group consisting ofphenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido,benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo,heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio,wherein: such substituent itself optionally is substituted with one ormore substituents selected from the group consisting of halogen,hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl,trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy,arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy,heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycrarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, N-monosubstituted aminohydrocarbyl,and N,N-disubstituted aminohydrocarbyl group, wherein; thesubstituent(s) on the monosubstituted or disubstituted aminohydrocarbylnitrogen is/are selected from the group consisting of hydrocarbyl, aryl,arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the substituents on thedisubstituted aminohydrocarbyl nitrogen, together with the disubstituteda aminohydrocarbyl nitrogen itself, form a 5- to 8-membered heterocyclicor heteroaryl ring group.
 26. The process according to claim 25 whereinR¹ is phenyl substituted with R³ at the 4-position, and R³ is a phenyl,phenoxy, anilino, thiophenoxy, phenylazo, benzamido, nicotinamido,isonicotinamido, picolinamido, or phenylureido group.
 27. The processaccording to claim 25 wherein the compound corresponds to:


28. The process according to claim 25 wherein said compound correspondsto:

wherein R³ is a phenyl, phenoxy, anilino, thiophenoxy, phenylazo,benzamido, nicotinamido, isonicotinamido, picolinamido, or phenylureidogroup, wherein: such substituent itself optionally is substituted withone or more substituents selected from the group consisting of halogen,hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl,trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy,arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy,heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroarylhydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, N-monosubstituted aminohydrocarbyl,and N,N-disubstituted aminohydrocarbyl group, wherein: thesubstituent(s) on the monosubstituted or disubstituted aminohydrocarbylnitrogen is/are selected from the group consisting of hydrocarbyl, aryl,arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the substituents on thedisubstituted aminohydrocarbyl nitrogen, together with the disubstitutedaminohydrocarbyl nitrogen itself, form a 5- to 8-membered heterocyclicor heteroaryl ring group.
 29. The compound according to claim 25 whereinsaid R³ is a phenoxy or thiophenoxy group that is unsubstituted.
 30. Theprocess according to claim 25 wherein said R² substituent is methyl,hydroxymethyl, methoxymethyl or (N-morpholino)methyl group.
 31. Theprocess according to claim 25 wherein said compound is an enantiomerwhose stereoconfiguration is as shown in the following formulas:


32. The process according to claim 25 wherein said compound isadministered a plurality of times.
 33. A process for treating a hostanimal having a condition associated with pathological matrixmetalloprotease activity that comprises administering a compound in anMMP enzyme-inhibiting effective amount to a mammalian host having such acondition, wherein the compound corresponds in structure to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbylC₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminoethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or N-thiomorpholino)methyl; and R³ is selectedfrom the group consisting of a single-ringed aryl group, a single-ringedheteroaryl group, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄ hydrocarbyloxygroup, a phenoxy group, a thiophenoxy group, an anilino group, a4-thiopyridyl group, a phenylazo group, a phenylureido, a nicotinamidogroup, an isonicotinamido group, a picolinamido group, and a benzamidogroup.
 34. A process for treating a host animal having a conditionassociated with pathological matrix metalloprotease activity thatcomprises administering a compound in an MMP enzyme-inhibiting effectiveamount to a mammalian host having such a condition, wherein the compoundcorresponds in structure to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is a phenyl,phenoxy, anilino, or thiophenoxy group that is optionally substituted:at the meta- or para-position or both with a moiety that is selectedfrom the group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, aC₁-C₁₀ hydrocarbyl group, a di-C₁-C₉ hydrocarbylamino group, a carboxylC₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbylgroup, and a C₁-C₈ hydrocarbyl carboxamido group, or at the meta- andpara-positions by two methyl groups or by a methylenedioxy group.
 35. Aprocess for treating a host animal having a condition associated withpathological matrix metalloprotease activity that comprisesadministering a compound in an MMP enzyme-inhibiting effective amount toa mammalian host having such a condition, wherein the compoundcorresponds in structure to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is benzamido,nicotinamido, isonicotinamido, picolinamido, or phenylureido, wherein:such substituent is optionally substituted at its own meta- or para-position with a moiety selected from the group consisting of a halogen anitro, a C₁-C₈ hydrocarbyl, a C₁-C₇ hydrocarbyloxy, an amino, and anamino-C₂-C₄-hydroxyalkyl group.
 36. A process for treating a host animalhaving a condition associated with pathological matrix metalloproteaseactivity that comprises administering a compound in an MMPenzyme-inhibiting effective amount to a mammalian host having such acondition, wherein the compound corresponds in structure to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is a phenyl,phenoxy, anilino, or thiophenoxy group that is itself substituted: atthe meta or para position or both with a moiety that is selected fromthe group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, aC₁-C₁₀ hydrocarbyl group, a di-C₁-C₉ hydrocarbylamino group, a carboxylC₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbylgroup, and a C₁-C₈-hydrocarbyl carboxamido group, or at the meta- andpara-positions by two methyl groups or by a alkylenedioxy group.
 37. Aprocess for treating a host animal ha a condition associated withpathological max metalloprotease activity that comprises administering acompound in an MMP enzyme-inhibiting effective amount to a mammalianhost having such a condition, wherein the compound corresponds instructure to:

wherein R² is hydrogen, C₁-C₄ hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxy, halo-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxymethyl, aminomethyl, (N—C₁-C₃ hydrocarbyl)aminomethyl,(N,N-di-C₁-C₃ hydrocarbyl)aminomethyl, (N-morpholino)methyl,(N-pyrrolidino)methyl, or (N-thiomorpholino)methyl; and R³ is abenzamido, nicotinamido, isonicotinamido, picolinamido, or phenylureidogroup, wherein: such substituent is substituted at its own meta- orpara-position with a moiety selected from the group consisting of ahalogen, a nitro, a C₁-C₈ hydrocarbyl, a C₁-C₇ hydrocarbyloxy, an amino,and an amino-C₂-C₄-hydroxyalkyl group.